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Entry
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- *138247 - GLUTAMATE RECEPTOR, IONOTROPIC, AMPA 2; GRIA2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*138247</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/138247">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000120251;t=ENST00000264426" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=2891" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=138247" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000120251;t=ENST00000264426" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000826,NM_001083619,NM_001083620,NM_001379000,NM_001379001,XM_047450131,XR_007096394" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001083619" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=138247" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=04726&isoform_id=04726_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/GRIA2" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/493134,6980911,6980912,14714846,23831146,62088714,73909236,119625270,119625271,119625272,119625273,119625274,119625275,119625276,217031267,217031269,217031271,217031273,217031275,217031277,217031279,217031281,217031283,217031285,221040022,353336544,1825727658,1825730066,1825761133,1825761138,1825761144,2217350353,2462596759,2462596761,2462596764,2462596766" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P42262" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=2891" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000120251;t=ENST00000264426" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=GRIA2" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=GRIA2" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+2891" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/GRIA2" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:2891" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2891" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr4&hgg_gene=ENST00000264426.14&hgg_start=157220120&hgg_end=157366075&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:4572" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=138247[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=138247[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/GRIA2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000120251" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=GRIA2" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=GRIA2" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GRIA2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=GRIA2&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA28967" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:4572" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0004619.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:95809" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/GRIA2#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:95809" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2891/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2891" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00001612;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00001612 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00001613;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00001613 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-020125-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2891" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=GRIA2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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138247
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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GLUTAMATE RECEPTOR, IONOTROPIC, AMPA 2; GRIA2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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GLUTAMATE RECEPTOR 2; GLUR2<br />
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GLURB
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GRIA2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GRIA2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/4/634?start=-3&limit=10&highlight=634">4q32.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:157220120-157366075&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">4:157,220,120-157,366,075</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/4/634?start=-3&limit=10&highlight=634">
|
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4q32.1
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Neurodevelopmental disorder with language impairment and behavioral abnormalities
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/618917"> 618917 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/138247" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/138247" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>Glutamate receptors sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) are ligand-activated cation channels that mediate the fast component of excitatory postsynaptic currents in neurons of the central nervous system. These channels are assembled from 4 related subunits, GLURA (GRIA1; <a href="/entry/138248">138248</a>), GLURB (GRIA2), GLURC (GRIA3; <a href="/entry/305915">305915</a>), GLURD (GRIA4; <a href="/entry/138246">138246</a>), with the GLURB subunit rendering the channel almost impermeable to Ca(2+) (<a href="#13" class="mim-tip-reference" title="Hollmann, M., Hartley, M., Heinemann, S. <strong>Ca(2+) permeability of KA-AMPA-gated glutamate receptor channels depends on subunit composition.</strong> Science 252: 851-853, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1709304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1709304</a>] [<a href="https://doi.org/10.1126/science.1709304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1709304">Hollmann et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1709304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By PCR of a human brain cDNA library using primers based on rat glutamate receptors, <a href="#29" class="mim-tip-reference" title="Sun, W., Ferrer-Montiel, A. V., Schinder, A. F., McPherson, J. P., Evans, G. A., Montal, M. <strong>Molecular cloning, chromosomal mapping, and functional expression of human brain glutamate receptors.</strong> Proc. Nat. Acad. Sci. 89: 1443-1447, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1311100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1311100</a>] [<a href="https://doi.org/10.1073/pnas.89.4.1443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1311100">Sun et al. (1992)</a> obtained a partial cDNA corresponding to approximately two-thirds of the coding region of a receptor homologous to rat brain Glur2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1311100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The C-terminal halves of the GLUR channels contain 4 transmembrane regions. <a href="#26" class="mim-tip-reference" title="Sommer, B., Keinanen, K., Verdoorn, T. A., Wisden, W., Burnashev, N., Herb, A., Kohler, M., Takagi, T., Sakmann, B., Seeburg, P. H. <strong>Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS.</strong> Science 249: 1580-1585, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1699275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1699275</a>] [<a href="https://doi.org/10.1126/science.1699275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1699275">Sommer et al. (1990)</a> determined that a small segment preceding the fourth transmembrane region in each GLUR channel subunit exists in 2 versions that have different amino acid sequences. These modules, designated 'flip' and 'flop,' are encoded by adjacent exons. About half of the GLUR cDNAs isolated from rat brain libraries specified the flip sequence, and the other half specified the flop sequence. Within rat brain, the flip versions of GLURA, GLURB, and GLURC were detected in CA3 neurons of the hippocampus, while both versions of these receptors and GLURD were found in CA1 neurons. Other central nervous system regions showed differential expression of flip and flop modules for each of the GLUR genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1699275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using in situ hybridization, <a href="#18" class="mim-tip-reference" title="McLaughlin, D. P., Cheetham, M. E., Kerwin, R. W. <strong>Expression of alternatively-spliced glutamate receptors in human hippocampus.</strong> Europ. J. Pharm. 244: 89-92, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8420792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8420792</a>] [<a href="https://doi.org/10.1016/0922-4106(93)90062-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8420792">McLaughlin et al. (1993)</a> found that expression of GLURA and GLURB in human hippocampus differed from their expression in rat hippocampus. In human, both genes were preferentially expressed in the dentate gyrus and CA1 regions, with lower expression in CA3. An exception was GLURB flop, which showed lower expression in CA3 than in dentate gyrus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8420792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#26" class="mim-tip-reference" title="Sommer, B., Keinanen, K., Verdoorn, T. A., Wisden, W., Burnashev, N., Herb, A., Kohler, M., Takagi, T., Sakmann, B., Seeburg, P. H. <strong>Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS.</strong> Science 249: 1580-1585, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1699275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1699275</a>] [<a href="https://doi.org/10.1126/science.1699275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1699275">Sommer et al. (1990)</a> determined that the flip and flop versions of the rat GLUR genes impart different pharmacologic and kinetic properties on currents evoked by L-glutamate or AMPA, but they do not differ in their response to kainate. The authors concluded that the exon switching may underlie adaptive changes in neurons such as synaptic plasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1699275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Paschen, W., Hedreen, J. C., Ross, C. A. <strong>RNA editing of the glutamate receptor subunits GluR2 and GluR6 in human brain tissue.</strong> J. Neurochem. 63: 1596-1602, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7523595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7523595</a>] [<a href="https://doi.org/10.1046/j.1471-4159.1994.63051596.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7523595">Paschen et al. (1994)</a> demonstrated RNA editing, posttranscriptional change of the sequence at the mRNA level, in human GLUR2 and GLUR6 (GRIK2; <a href="/entry/138244">138244</a>), as had previously been demonstrated in rats. A CAG, coding for glutamine within the putative second transmembrane domain of GLUR2, is changed to CGG, coding for arginine in the mRNA sequence. As in the rat, the GLUR2 subunit mRNA is completely edited in human brain. However, GLUR6 is only 10% edited in the corpus callosum and 90% edited in the gray matter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7523595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In rat hippocampal pyramidal neurons, <a href="#8" class="mim-tip-reference" title="Daw, M. I., Chittajallu, R., Bortolotto, Z. A., Dev, K. K., Duprat, F., Henley, J. M., Collingridge, G. L., Isaac, J. T. R. <strong>PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses.</strong> Neuron 28: 873-886, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11163273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11163273</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)00160-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11163273">Daw et al. (2000)</a> demonstrated that interruption of the interaction between C-terminal Glur2 and PDZ domain-containing proteins, such as GRIP (<a href="/entry/603597">603597</a>) and PICK1 (<a href="/entry/605926">605926</a>), resulted in increased AMPA receptor-mediated excitatory transmission and blockade of long-term depression. Inhibition of protein kinase C (PKC; see <a href="/entry/176960">176960</a>) prevented these effects. <a href="#8" class="mim-tip-reference" title="Daw, M. I., Chittajallu, R., Bortolotto, Z. A., Dev, K. K., Duprat, F., Henley, J. M., Collingridge, G. L., Isaac, J. T. R. <strong>PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses.</strong> Neuron 28: 873-886, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11163273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11163273</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)00160-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11163273">Daw et al. (2000)</a> proposed a model in which the maintenance of long-term depression involves the binding of AMPA receptors, via the Glur2 subunit, to PDZ proteins to prevent their reinsertion, and that protein kinase C plays a role in receptor insertion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11163273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By analyzing subcellular distribution and endoplasmic reticulum (ER) export kinetics, <a href="#10" class="mim-tip-reference" title="Greger, I. H., Khatri, L., Ziff, E. B. <strong>RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum.</strong> Neuron 34: 759-772, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12062022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12062022</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00693-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12062022">Greger et al. (2002)</a> showed that, unlike GluR1, GluR2 remains partly in an intracellular pool in the ER and is extensively complexed with GluR3 in rat brain. Using mutagenesis, <a href="#10" class="mim-tip-reference" title="Greger, I. H., Khatri, L., Ziff, E. B. <strong>RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum.</strong> Neuron 34: 759-772, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12062022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12062022</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00693-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12062022">Greger et al. (2002)</a> showed that elements in the C terminus of GluR2, including the PDZ motif, are required for GluR2 forward-transport from the ER. The authors found that ER retention of GluR2 was controlled by arg607 (R607) at the Q/R editing site. Reversion of this residue to gln (R607Q), as is found in GluR1, resulted in GluR1-like rapid release from the ER pool and elevated surface expression of GluR2 in neurons. <a href="#10" class="mim-tip-reference" title="Greger, I. H., Khatri, L., Ziff, E. B. <strong>RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum.</strong> Neuron 34: 759-772, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12062022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12062022</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00693-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12062022">Greger et al. (2002)</a> concluded that the arg607 residue of GluR2 controls exit from the ER and may thereby ensure the availability of GluR2 for assembly into AMPA receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12062022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Cerebellar long-term depression is a model of synaptic memory that requires protein kinase C (PKC) activation and is expressed as a reduction in the number of postsynaptic AMPA receptors (AMPARs). <a href="#6" class="mim-tip-reference" title="Chung, H. J., Steinberg, J. P., Huganir, R. L., Linden, D. J. <strong>Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression.</strong> Science 300: 1751-1755, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12805550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12805550</a>] [<a href="https://doi.org/10.1126/science.1082915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12805550">Chung et al. (2003)</a> found that long-term depression was absent in cultured cerebellar Purkinje cells from mutant mice lacking the AMPAR GluR2 subunit and could be rescued by transient transfection with the wildtype GluR2 subunit. Transfection with GluR2 carrying a point mutation that eliminated PKC phosphorylation of ser880 in the carboxy-terminal PDZ ligand of GluR2 failed to restore long-term depression. In contrast, transfection with GluR2 carrying a point mutation that mimicked phosphorylation at ser880 occluded subsequent long-term depression. Thus, PKC phosphorylation of GluR2 on ser880 is a critical event in the induction of cerebellar long-term depression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12805550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The abundance of postsynaptic AMPARs correlates with the size of the synapse and the dimensions of the dendritic spine head. Moreover, long-term potentiation is associated with formation of dendritic spines as well as synaptic delivery of AMPARs. <a href="#23" class="mim-tip-reference" title="Passafaro, M., Nakagawa, T., Sala, C., Sheng, M. <strong>Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2.</strong> Nature 424: 677-681, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12904794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12904794</a>] [<a href="https://doi.org/10.1038/nature01781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12904794">Passafaro et al. (2003)</a> demonstrated that overexpression of GLUR2 increases dendritic spine size and density in hippocampal neurons, and more remarkably, induces spine formation in GABA-releasing interneurons that normally lack spines. The extracellular N-terminal domain of GLUR2 is responsible for this effect, and heterologous fusion proteins of the N-terminal domain of GLUR2 inhibit spine morphogenesis. <a href="#23" class="mim-tip-reference" title="Passafaro, M., Nakagawa, T., Sala, C., Sheng, M. <strong>Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2.</strong> Nature 424: 677-681, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12904794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12904794</a>] [<a href="https://doi.org/10.1038/nature01781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12904794">Passafaro et al. (2003)</a> proposed that the N-terminal domain of GLUR2 functions at the cell surface as part of a receptor-ligand interaction that is important for spine growth and/or stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12904794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Sutton, M. A., Schmidt, E. F., Choi, K.-H., Schad, C. A., Whisler, K., Simmons, D., Karanian, D. A., Monteggia, L. M., Neve, R. L., Self, D. W. <strong>Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour.</strong> Nature 421: 70-75, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12511956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12511956</a>] [<a href="https://doi.org/10.1038/nature01249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12511956">Sutton et al. (2003)</a> demonstrated that extinction training during the withdrawal from chronic cocaine self-administration in rats induces experience-dependent increases in the GLUR1 and GLUR2/3 subunits of AMPA glutamate receptors in the nucleus accumbens shell, a brain region that is critically involved in cocaine reward. Increases in the GLUR1 subunit were positively associated with a level of extinction achieved during training, suggesting that GLUR1 may promote extinction of cocaine seeking. <a href="#31" class="mim-tip-reference" title="Sutton, M. A., Schmidt, E. F., Choi, K.-H., Schad, C. A., Whisler, K., Simmons, D., Karanian, D. A., Monteggia, L. M., Neve, R. L., Self, D. W. <strong>Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour.</strong> Nature 421: 70-75, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12511956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12511956</a>] [<a href="https://doi.org/10.1038/nature01249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12511956">Sutton et al. (2003)</a> showed that viral-mediated overexpression of both GLUR1 and GLUR2 in nucleus accumbens shell neurons facilitates extinction of cocaine- but not sucrose-seeking responses. A single extinction training session, when conducted during GLUR subunit overexpression, attenuated stress-induced relapse to cocaine seeking even after GLUR overexpression declined. <a href="#31" class="mim-tip-reference" title="Sutton, M. A., Schmidt, E. F., Choi, K.-H., Schad, C. A., Whisler, K., Simmons, D., Karanian, D. A., Monteggia, L. M., Neve, R. L., Self, D. W. <strong>Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour.</strong> Nature 421: 70-75, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12511956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12511956</a>] [<a href="https://doi.org/10.1038/nature01249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12511956">Sutton et al. (2003)</a> concluded that extinction-induced plasticity in AMPARs may facilitate control over cocaine seeking by restoring glutamatergic tone in the nucleus accumbens, and may reduce the propensity for relapse under stressful situations in prolonged abstinence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12511956" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Kawahara, Y., Ito, K., Sun, H., Aizawa, H., Kanazawa, I., Kwak, S. <strong>RNA editing and death of motor neurons: there is a glutamate-receptor defect in patients with amyotrophic lateral sclerosis. (Letter)</strong> Nature 427: 801 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14985749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14985749</a>] [<a href="https://doi.org/10.1038/427801a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14985749">Kawahara et al. (2004)</a> extracted RNA from single motor neurons isolated with a laser microdissector from 5 individuals with sporadic amyotrophic lateral sclerosis (ALS1; <a href="/entry/105400">105400</a>) and 5 normal control subjects. GluR2 RNA editing was 100% efficient in the control samples, but the editing efficiency varied between 0 and 100% in the motor neurons from each individual with ALS and was incomplete in 44 of them (56%). Mice transgenic for GluR2 made artificially permeable to calcium ions developed motor neuron disease late in life (<a href="#9" class="mim-tip-reference" title="Feldmeyer, D., Kask, K., Brusa, R., Kornau, H.-C., Kolhekar, R., Rozov, A., Burnashev, N., Jensen, V., Hvalby, O., Sprengel, R., Seeburg, P. H. <strong>Neurological dysfunctions in mice expressing different levels of the Q/R site-unedited AMPAR subunit GluR-B.</strong> Nature Neurosci. 2: 57-64, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10195181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10195181</a>] [<a href="https://doi.org/10.1038/4561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10195181">Feldmeyer et al., 1999</a>), indicating that motor neurons may be specifically vulnerable to defective RNA editing. <a href="#14" class="mim-tip-reference" title="Kawahara, Y., Ito, K., Sun, H., Aizawa, H., Kanazawa, I., Kwak, S. <strong>RNA editing and death of motor neurons: there is a glutamate-receptor defect in patients with amyotrophic lateral sclerosis. (Letter)</strong> Nature 427: 801 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14985749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14985749</a>] [<a href="https://doi.org/10.1038/427801a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14985749">Kawahara et al. (2004)</a> suggested that defective GluR2 RNA editing at the Q/R site may be relevant to ALS etiology. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14985749+10195181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Phosphorylation of GluR1 (GRIA1; <a href="/entry/138248">138248</a>) by CaMKII (see CAMK2A; <a href="/entry/114078">114078</a>) increases conductance of homodimeric GluR1 channels. In rat, <a href="#20" class="mim-tip-reference" title="Oh, M. C., Derkach, V. A. <strong>Dominant role of the GluR2 subunit in regulation of AMPA receptors by CaMKII.</strong> Nature Neurosci. 8: 853-854, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15924137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15924137</a>] [<a href="https://doi.org/10.1038/nn1476" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15924137">Oh and Derkach (2005)</a> found that incorporation of GluR2 in GluR1/GluR2 heterodimers disrupted the coupling between GluR1 phosphorylation and channel conductance, keeping the GluR1/GluR2 heteromers in low conductance state regardless of GluR1 phosphorylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15924137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>At rat cerebellar parallel fiber-stellate cell synapses, Ca(2+) influx through Glur2-lacking AMPARs drives incorporation of Ca(2+)-impermeable Glur2-containing AMPARs, generating rapid changes in excitatory postsynaptic current properties. <a href="#16" class="mim-tip-reference" title="Liu, S. J., Cull-Candy, S. G. <strong>Subunit interaction with PICK and GRIP controls Ca(2+) permeability of AMPARs at cerebellar synapses.</strong> Nature Neurosci. 8: 768-775, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15895086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15895086</a>] [<a href="https://doi.org/10.1038/nn1468" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15895086">Liu and Cull-Candy (2005)</a> found that repetitive synaptic activity triggered loss of Glur2-lacking AMPARs by disrupting their interaction with Grip (GRIP1; <a href="/entry/604597">604597</a>). Pick (PICK1; <a href="/entry/605926">605926</a>) drove activity-dependent delivery of Glur2-containing AMPARs into the synaptic membrane. <a href="#16" class="mim-tip-reference" title="Liu, S. J., Cull-Candy, S. G. <strong>Subunit interaction with PICK and GRIP controls Ca(2+) permeability of AMPARs at cerebellar synapses.</strong> Nature Neurosci. 8: 768-775, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15895086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15895086</a>] [<a href="https://doi.org/10.1038/nn1468" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15895086">Liu and Cull-Candy (2005)</a> concluded that dynamic regulation of AMPARs by GRIP and PICK provides a mechanism for controlling Ca(2+) permeability of synaptic receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15895086" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Metabotropic glutamate receptor (see <a href="/entry/604099">604099</a>)-dependent long-term depression in the ventral tegmental area efficiently reverses cocaine-induced strengthening of excitatory inputs onto dopamine neurons. <a href="#17" class="mim-tip-reference" title="Mameli, M., Balland, B., Lujan, R., Luscher, C. <strong>Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area.</strong> Science 317: 530-533, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17656725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17656725</a>] [<a href="https://doi.org/10.1126/science.1142365" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17656725">Mameli et al. (2007)</a> showed that metabotropic glutamate receptor long-term depression is expressed by an exchange of GluR2-lacking AMPA receptors for GluR2-containing receptors with a lower single-channel conductance. The synaptic insertion of GluR2 depends on de novo protein synthesis via rapid mRNA translation of GluR2. <a href="#17" class="mim-tip-reference" title="Mameli, M., Balland, B., Lujan, R., Luscher, C. <strong>Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area.</strong> Science 317: 530-533, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17656725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17656725</a>] [<a href="https://doi.org/10.1126/science.1142365" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17656725">Mameli et al. (2007)</a> concluded that regulated synthesis of GluR2 in the ventral tegmental area is required to reverse cocaine-induced synaptic plasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17656725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Panicker, S., Brown, K., Nicoll, R. A. <strong>Synaptic AMPA receptor subunit trafficking is independent of the C terminus in the GluR2-lacking mouse.</strong> Proc. Nat. Acad. Sci. 105: 1032-1037, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18195349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18195349</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18195349[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0711313105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18195349">Panicker et al. (2008)</a> found that the C terminus of mouse Glur2 was not required for Glur2 synaptic insertion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18195349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Biou, V., Bhattacharyya, S., Malenka, R. C. <strong>Endocytosis and recycling of AMPA receptors lacking GluR2/3.</strong> Proc. Nat. Acad. Sci. 105: 1038-1043, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18195348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18195348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18195348[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0711412105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18195348">Biou et al. (2008)</a> found that AMPA receptors lacking Glur2 and Glur3 were permeable to calcium and that this permeability influenced the subcellular sites in cultured mouse hippocampal neurons at which activity-dependent AMPA receptor endocytosis occurred. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18195348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Panicker, S., Brown, K., Nicoll, R. A. <strong>Synaptic AMPA receptor subunit trafficking is independent of the C terminus in the GluR2-lacking mouse.</strong> Proc. Nat. Acad. Sci. 105: 1032-1037, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18195349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18195349</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18195349[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0711313105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18195349">Panicker et al. (2008)</a> and <a href="#2" class="mim-tip-reference" title="Biou, V., Bhattacharyya, S., Malenka, R. C. <strong>Endocytosis and recycling of AMPA receptors lacking GluR2/3.</strong> Proc. Nat. Acad. Sci. 105: 1038-1043, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18195348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18195348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18195348[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0711412105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18195348">Biou et al. (2008)</a> noted that RNA editing resulting in a switch of Q607 to R607 in GLUR2 controls the assembly of GLUR2-containing AMPA receptors and makes them impermeable to calcium and resistant to block by polyamines. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18195348+18195349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Conrad, K. L., Tseng, K. Y., Uejima, J. L., Reimers, J. M., Heng, L.-J., Shaham, Y., Marinelli, M., Wolf, M. E. <strong>Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving.</strong> Nature 454: 118-121, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18500330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18500330</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18500330[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature06995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18500330">Conrad et al. (2008)</a> showed that the number of synaptic AMPA receptors in the accumbens is increased after prolonged withdrawal from cocaine self-administration by the addition of new AMPA receptors lacking GluR2. Furthermore, they showed that these new receptors mediate the incubation of cocaine craving. The results indicate that GluR2-lacking AMPA receptors could be a new target for drug development for the treatment of cocaine addiction. <a href="#7" class="mim-tip-reference" title="Conrad, K. L., Tseng, K. Y., Uejima, J. L., Reimers, J. M., Heng, L.-J., Shaham, Y., Marinelli, M., Wolf, M. E. <strong>Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving.</strong> Nature 454: 118-121, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18500330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18500330</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18500330[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature06995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18500330">Conrad et al. (2008)</a> proposed that after prolonged withdrawal from cocaine, increased numbers of synaptic AMPA receptors combined with the higher conductance of GluR2-lacking AMPA receptors causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18500330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#1" class="mim-tip-reference" title="Armstrong, N., Gouaux, E. <strong>Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core.</strong> Neuron 28: 165-181, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11086992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11086992</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)00094-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11086992">Armstrong and Gouaux (2000)</a> determined the crystal structures of the GLUR2 ligand-binding core in the apo state and in the presence of the antagonist DNQX, the partial agonist kainate, and the full agonists AMPA and glutamate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11086992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Sobolevsky, A. I., Rosconi, M. P., Gouaux, E. <strong>X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.</strong> Nature 462: 745-756, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19946266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19946266</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19946266[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08624" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19946266">Sobolevsky et al. (2009)</a> reported the crystal structure of the rat GluA2 receptor at 3.6-angstrom resolution in complex with a competitive antagonist. The receptor harbors an overall axis of 2-fold symmetry with the extracellular domains organized as pairs of local dimers and with the ion channel domain exhibiting 4-fold symmetry. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19946266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Chen, L., Durr, K. L., Gouaux, E. <strong>X-ray structures of AMPA receptor-cone snail toxin complexes illuminate activation mechanism.</strong> Science 345: 1021-1026, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25103405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25103405</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25103405[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1258409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25103405">Chen et al. (2014)</a> determined multiple x-ray crystal structures of the GluA2 AMPA receptor in complex with a Conus striatus cone snail toxin, a positive allosteric modulator, and orthosteric agonists, at 3.8- to 4.1-angstrom resolution. The authors showed how the toxin acts like a straitjacket on the ligand-binding domain (LBD) 'gating ring,' restraining the domains via both intra- and interdimer crosslinks such that agonist-induced closure of the LBD 'clamshells' is transduced into an iris-like expansion of the gating ring. By structural analysis of activation-enhancing mutants, <a href="#4" class="mim-tip-reference" title="Chen, L., Durr, K. L., Gouaux, E. <strong>X-ray structures of AMPA receptor-cone snail toxin complexes illuminate activation mechanism.</strong> Science 345: 1021-1026, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25103405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25103405</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25103405[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1258409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25103405">Chen et al. (2014)</a> showed how the expansion of the LBD gating ring results in pulling forces on the M3 helices that, in turn, are coupled to ion channel gating. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25103405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Yelshanskaya, M. V., Li, M., Sobolevsky, A. I. <strong>Structure of an agonist-bound ionotropic glutamate receptor.</strong> Science 345: 1070-1074, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25103407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25103407</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25103407[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1256508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25103407">Yelshanskaya et al. (2014)</a> reported a structure of a homotetrameric rat GluA2 receptor in complex with partial agonist (S)-5-nitrowillardiine. Comparison of this structure with the closed-state structure in complex with competitive antagonist ZK 200775 suggested conformational changes that occur during ionotropic glutamate receptor (iGluR) gating. Guided by the structures, <a href="#33" class="mim-tip-reference" title="Yelshanskaya, M. V., Li, M., Sobolevsky, A. I. <strong>Structure of an agonist-bound ionotropic glutamate receptor.</strong> Science 345: 1070-1074, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25103407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25103407</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25103407[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1256508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25103407">Yelshanskaya et al. (2014)</a> engineered disulfide crosslinks to probe domain interactions that are important for iGluR gating events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25103407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Sun, Y., Olson, R., Horning, M., Armstrong, N., Mayer, M., Gouaux, E. <strong>Mechanism of glutamate receptor desensitization.</strong> Nature 417: 245-253, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12015593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12015593</a>] [<a href="https://doi.org/10.1038/417245a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12015593">Sun et al. (2002)</a> demonstrated a mechanism of desensitization of AMPA glutamate receptors. Using the GluR2 AMPA-sensitive glutamate receptor, <a href="#30" class="mim-tip-reference" title="Sun, Y., Olson, R., Horning, M., Armstrong, N., Mayer, M., Gouaux, E. <strong>Mechanism of glutamate receptor desensitization.</strong> Nature 417: 245-253, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12015593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12015593</a>] [<a href="https://doi.org/10.1038/417245a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12015593">Sun et al. (2002)</a> showed that the ligand-binding cores form dimers and that stabilization of the intradimer interface by either mutations or allosteric modulators reduces desensitization. Perturbations that destabilize the interface enhance desensitization. Receptor activation involves conformational changes within each subunit that result in an increase in the separation of portions of the receptor that are linked to the ion channel. <a href="#30" class="mim-tip-reference" title="Sun, Y., Olson, R., Horning, M., Armstrong, N., Mayer, M., Gouaux, E. <strong>Mechanism of glutamate receptor desensitization.</strong> Nature 417: 245-253, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12015593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12015593</a>] [<a href="https://doi.org/10.1038/417245a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12015593">Sun et al. (2002)</a> concluded that their analysis defines the dimer interface in the resting and activated state, indicates how ligand binding is coupled to gating, and suggests modes of dimer-dimer interaction in the assembled tetramer. Desensitization occurs through rearrangement of the dimer interface, which disengages the agonist-induced conformational change in the ligand-binding core from the ion channel gate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12015593" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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<a href="#12" class="mim-tip-reference" title="Herguedas, B., Watson, J. F., Ho, H., Cais, O., Garcia-Nafria, J., Greger, I. H. <strong>Architecture of the heteromeric GluA1/2 AMPA receptor in complex with the auxiliary subunit TARP gamma-8.</strong> Science 364: eaav9011, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30872532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30872532</a>] [<a href="https://doi.org/10.1126/science.aav9011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30872532">Herguedas et al. (2019)</a> presented a cryoelectron microscopy structure of the heteromeric GluA1 (<a href="/entry/138248">138248</a>)/GluA2 receptor associated with 2 transmembrane AMPAR regulatory protein (TARP) gamma-8 (<a href="/entry/606900">606900</a>) auxiliary subunits, the principal AMPAR complex at hippocampal synapses. Within the receptor, the core subunits arrange to give the GluA2 subunit dominant control of gating. This structure revealed the geometry of the Q/R site that controls calcium flux, suggested association of TARP-stabilized lipids, and demonstrated that the extracellular loop of gamma-8 modulates gating by selectively interacting with the GluA2 ligand-binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30872532" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Zhao, Y., Chen, S., Swensen, A. C., Qian, W. J., Gouaux, E. <strong>Architecture and subunit arrangement of native AMPA receptors elucidated by cryo-EM.</strong> Science 364: 355-362, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30975770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30975770</a>] [<a href="https://doi.org/10.1126/science.aaw8250" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30975770">Zhao et al. (2019)</a> elucidated the structures of 10 distinct native AMPA receptor complexes by single-particle cryoelectron microscopy and found that receptor subunits are arranged nonstochastically, with the GluA2 subunit preferentially occupying the B and D positions of the tetramer and with triheteromeric assemblies comprising a major population of native AMPA receptors. GluA1 predominantly accesses the A or C positions. Cryo-EM maps define the structure for S2-M4 linkers between the ligand-binding and transmembrane domains, suggesting how neurotransmitter binding is coupled to ion channel gating. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30975770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By PCR analysis of somatic cell hybrid cell lines, <a href="#29" class="mim-tip-reference" title="Sun, W., Ferrer-Montiel, A. V., Schinder, A. F., McPherson, J. P., Evans, G. A., Montal, M. <strong>Molecular cloning, chromosomal mapping, and functional expression of human brain glutamate receptors.</strong> Proc. Nat. Acad. Sci. 89: 1443-1447, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1311100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1311100</a>] [<a href="https://doi.org/10.1073/pnas.89.4.1443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1311100">Sun et al. (1992)</a> assigned the GLUR2 gene to chromosome 4. Use of a panel of 7 additional cell hybrids containing various deletions of chromosome 4 permitted sublocalization to 4q25-q34.3. A pseudogene or related gene appeared to be situated on chromosome 8. <a href="#19" class="mim-tip-reference" title="McNamara, J. O., Eubanks, J. H., McPherson, J. D., Wasmuth, J. J., Evans, G. A., Heinemann, S. F. <strong>Chromosomal localization of human glutamate receptor genes.</strong> J. Neurosci. 12: 2555-2562, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1319477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1319477</a>] [<a href="https://doi.org/10.1523/JNEUROSCI.12-07-02555.1992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1319477">McNamara et al. (1992)</a> narrowed the assignment to 4q32-q33 by fluorescence in situ suppression hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1311100+1319477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 06/24/2020."None>Stumpf (2020)</a> mapped the GRIA2 gene to chromosome 4q32.1 based on an alignment of the GRIA2 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC010574" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC010574</a>) with the genomic sequence (GRCh38).</p><p>Using PCR with a panel of DNA from an interspecific backcross, and through RFLV and haplotype analyses, <a href="#11" class="mim-tip-reference" title="Gregor, P., Reeves, R. H., Jabs, E. W., Yang, X., Dackowski, W., Rochelle, J. M., Brown, R. H., Jr., Haines, J. L., O'Hara, B. F., Uhl, G. R., Seldin, M. F. <strong>Chromosomal localization of glutamate receptor genes: relationship to familial amyotrophic lateral sclerosis and other neurological disorders of mice and humans.</strong> Proc. Nat. Acad. Sci. 90: 3053-3057, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8464923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8464923</a>] [<a href="https://doi.org/10.1073/pnas.90.7.3053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8464923">Gregor et al. (1993)</a> mapped the Glur2 gene in the mouse to a region of chromosome 3 that contains the 'spastic' mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8464923" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 25 unrelated patients with neurodevelopmental disorder with language impairment and behavioral abnormalities (NEDLIB; <a href="/entry/618917">618917</a>), <a href="#24" class="mim-tip-reference" title="Salpietro, V., Dixon, C. L., Guo, H., Bello, O. D., Vandrovcova, J., Efthymiou, S., Maroofian, R., Heimer, G., Burglen, L., Valence, S., Torti, E., Hacke, M., and 80 others. <strong>AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.</strong> Nature Commun. 10: 3094, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31300657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31300657</a>] [<a href="https://doi.org/10.1038/s41467-019-10910-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31300657">Salpietro et al. (2019)</a> identified de novo heterozygous mutations in the GRIA2 gene (see, e.g., <a href="#0001">138247.0001</a>-<a href="#0006">138247.0006</a>). There were 15 missense, 2 splice site, and 1 nonsense mutation, 1 in-frame deletion, and 2 frameshift variants; mutations occurred throughout the gene. The mutations, which were found by whole-genome, whole-exome, or targeted sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed variable effects of the mutations. Seven of 11 mutations caused a decreased agonist-induced current compared to wildtype, 3 mutations had normal current amplitudes, and 1 resulted in an increase in current amplitude. When coexpressed with GRIA1 (<a href="/entry/138248">138248</a>), most of the mutant proteins showed a decreased current amplitude compared to wildtype, and some affected rectification. Some mutations reduced the GRIA2 surface expression, suggesting that defects in heteromerization or cell surface trafficking may be another important pathogenic mechanism. Overall, most of the mutations appeared to result in a loss of function. No clear genotype/phenotype correlations emerged, although 2 patients who died in infancy both carried the same variant (A639S; <a href="#0005">138247.0005</a>). <a href="#24" class="mim-tip-reference" title="Salpietro, V., Dixon, C. L., Guo, H., Bello, O. D., Vandrovcova, J., Efthymiou, S., Maroofian, R., Heimer, G., Burglen, L., Valence, S., Torti, E., Hacke, M., and 80 others. <strong>AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.</strong> Nature Commun. 10: 3094, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31300657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31300657</a>] [<a href="https://doi.org/10.1038/s41467-019-10910-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31300657">Salpietro et al. (2019)</a> emphasized the biologic diversity of the tested mutants, and suggested that phenotypic differences may arise from different effects of distinct mutations. The report implicated GRIA2 dysfunction and disruption of glutamatergic synaptic transmission in neurodevelopmental disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31300657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The molecular determinant of the dominant property of the GLURB subunit in rendering the AMPA-sensitive channels impermeable to calcium can be traced to the arginine residue at position 586 of the mature subunit, which lies within the pore-forming segment M2. This arginine is not gene encoded but is posttranscriptionally introduced into GLURB pre-mRNA by site-selective adenosine deamination, which leads to the change of a CAA glutamine (Q) codon to a codon for arginine (R) in more than 99% of mRNA molecules. Termed Q/R site editing, this nuclear process depends on a double-stranded RNA structure formed in the pre-mRNA by the editing site in exon 11 and the editing site complementary sequence (ECS) in intron 11 (<a href="#15" class="mim-tip-reference" title="Kohler, M., Kornau, H. C., Seeburg, P. H. <strong>The organization of the gene for the functionally dominant alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit Glu4-B.</strong> J. Biol. Chem. 269: 17367-17370, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7545935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7545935</a>]" pmid="7545935">Kohler et al., 1994</a>). To investigate in an animal model the relevance of this process for central nervous system physiology, <a href="#3" class="mim-tip-reference" title="Brusa, R., Zimmermann, F., Koh, D.-S., Feldmeyer, D., Gass, P., Seeburg, P. H., Sprengel, R. <strong>Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice.</strong> Science 270: 1677-1680, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7502080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7502080</a>] [<a href="https://doi.org/10.1126/science.270.5242.1677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7502080">Brusa et al. (1995)</a> targeted intron 11 of the Glur2 gene in mouse ES cells for replacement of the ECS element, and then injected correctly engineered cells into C57BL/6 blastocysts. One of several resultant chimeric animals showed vertical transmission of the knockout allele in a mendelian fashion, indicating that the allele did not adversely affect embryonic development. Heterozygous mice synthesized unedited GLURB subunits and, in principal neurons and interneurons, expressed AMPA receptors with increased calcium permeability. These mice developed seizures and died by 3 weeks of age, suggesting to <a href="#3" class="mim-tip-reference" title="Brusa, R., Zimmermann, F., Koh, D.-S., Feldmeyer, D., Gass, P., Seeburg, P. H., Sprengel, R. <strong>Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice.</strong> Science 270: 1677-1680, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7502080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7502080</a>] [<a href="https://doi.org/10.1126/science.270.5242.1677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7502080">Brusa et al. (1995)</a> that GLURB pre-mRNA editing is essential for brain function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7545935+7502080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Amyotrophic lateral sclerosis (ALS; see <a href="/entry/105400">105400</a>) is a neurodegenerative disorder characterized by cell death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. Approximately 15 to 20% of cases of familial ALS are associated with mutations in the superoxide dismutase-1 gene, SOD1 (<a href="/entry/147450">147450</a>). To evaluate the contribution of motoneuronal Ca(2+)-permeable (GluR2 subunit-lacking) alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors to SOD1-related motoneuronal death, <a href="#32" class="mim-tip-reference" title="Tateno, M., Sadakata, H., Tanaka, M., Itohara, S., Shin, R.-M., Miura, M., Masuda, M., Aosaki, T., Urushitani, M., Misawa, H., Takahashi, R. <strong>Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model.</strong> Hum. Molec. Genet. 13: 2183-2196, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15294873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15294873</a>] [<a href="https://doi.org/10.1093/hmg/ddh246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15294873">Tateno et al. (2004)</a> generated choline acetyltransferase (ChAT; <a href="/entry/118490">118490</a>)-GluR2 transgenic mice with significantly reduced Ca(2)+ permeability of these receptors in spinal motoneurons. Crossbreeding of the Sod1(G93A) transgenic mouse model of ALS with ChAT-GluR2 mice led to marked delay of disease onset, mortality, and the pathologic hallmarks such as release of cytochrome c from mitochondria, induction of cox2 (<a href="/entry/600262">600262</a>), and astrogliosis. Subcellular fractionation analysis revealed that unusual SOD1 species accumulated in 2 fractions (P1, composed of nuclei and certain kinds of cytoskeletons such as neurofilaments and glial fibrillary acidic protein (GFAP; <a href="/entry/137780">137780</a>), and P2, composed of mitochondria) long before disease onset and then extensively accumulated in the P1 fractions by disease onset. All these processes for unusual SOD1 accumulation were considerably delayed by GluR2 overexpression. Ca(2+) influx through atypical motoneuronal AMPA receptors thus promoted a misfolding of mutant SOD1 protein and eventual death of these neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15294873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Steinberg, J. P., Takamiya, K., Shen, Y., Xia, J., Rubio, M. E., Yu, S., Jin, W., Thomas, G. M., Linden, D. J., Huganir, R. L. <strong>Targeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression.</strong> Neuron 49: 845-860, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16543133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16543133</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.02.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16543133">Steinberg et al. (2006)</a> generated 2 lines of transgenic mice: Pick1 (<a href="/entry/605926">605926</a>)-null mice and those with targeted disruption of the C-terminal PDZ ligand of GluR2, which is a binding site of GluR2 to Pick1. Purkinje cells and cerebellar slices from both groups of mutant mice showed absence of cerebellar long-term depression (LTD). Rescue studies showed that the PDZ and the BAR domains of Pick1 were required for LTD. Phosphorylation at ser880 of GluR2 was also required for cerebellar LTD, as well as for proper GluR2 trafficking. Overall, the results indicated that Pick1-GluR2 PDZ-based interactions and GluR2 phosphorylation are required for cerebellar LTD expression in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16543133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Postsynaptic AMPA receptor desensitization plays a major role in depression at synapses in which glutamate remains in the synaptic cleft for prolonged periods of time during normal operation of the synapse. <a href="#5" class="mim-tip-reference" title="Christie, L. A., Russell, T. A., Xu, J., Wood, L., Shepherd, G. M. G., Contractor, A. <strong>AMPA receptor desensitization mutation results in severe developmental phenotypes and early postnatal lethality.</strong> Proc. Nat. Acad. Sci. 107: 9412-9417, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20439731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20439731</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20439731[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0908206107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20439731">Christie et al. (2010)</a> found that homozygous expression of a nondesensitizing point mutation, leu483 to tyr (L483Y), in the mouse Gria2 receptor subunit was embryonic lethal. Heterozygous mutant mice were initially viable, but they developed a severe neurologic and developmental phenotype that included significant runting, abnormal gait, progressively severe seizures, and mortality in the third postnatal week. Western blot and immunohistochemical analyses revealed drastic compensatory changes in glutamate receptor expression and reduced extrasynaptic AMPA receptor density in mutant mice. <a href="#5" class="mim-tip-reference" title="Christie, L. A., Russell, T. A., Xu, J., Wood, L., Shepherd, G. M. G., Contractor, A. <strong>AMPA receptor desensitization mutation results in severe developmental phenotypes and early postnatal lethality.</strong> Proc. Nat. Acad. Sci. 107: 9412-9417, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20439731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20439731</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20439731[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0908206107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20439731">Christie et al. (2010)</a> concluded that AMPA receptor desensitization is critical for viability and function of the central nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20439731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=138247[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p>In a 19-year-old man (patient 3) with neurodevelopmental disorder with language impairment and behavioral abnormalities (NEDLIB; <a href="/entry/618917">618917</a>), who had developmental regression starting in late childhood, <a href="#24" class="mim-tip-reference" title="Salpietro, V., Dixon, C. L., Guo, H., Bello, O. D., Vandrovcova, J., Efthymiou, S., Maroofian, R., Heimer, G., Burglen, L., Valence, S., Torti, E., Hacke, M., and 80 others. <strong>AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.</strong> Nature Commun. 10: 3094, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31300657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31300657</a>] [<a href="https://doi.org/10.1038/s41467-019-10910-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31300657">Salpietro et al. (2019)</a> identified a de novo heterozygous c.1831G-A transition (c.1831G-A, NM_000826.3) in exon 11 of the GRIA2 gene, resulting in an asp611-to-asn (D611N) substitution at a conserved residue in the transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed that the mutation did not significantly affect the current amplitude. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31300657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 19-year-old woman (patient 4) with neurodevelopmental disorder with language impairment and behavioral abnormalities (NEDLIB; <a href="/entry/618917">618917</a>), who had a history of developmental regression, <a href="#24" class="mim-tip-reference" title="Salpietro, V., Dixon, C. L., Guo, H., Bello, O. D., Vandrovcova, J., Efthymiou, S., Maroofian, R., Heimer, G., Burglen, L., Valence, S., Torti, E., Hacke, M., and 80 others. <strong>AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.</strong> Nature Commun. 10: 3094, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31300657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31300657</a>] [<a href="https://doi.org/10.1038/s41467-019-10910-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31300657">Salpietro et al. (2019)</a> identified a de novo heterozygous c.1825G-A transition (c.1825G-A, NM_000826.3) in exon 11 of the GRIA2 gene, resulting in a gly609-to-arg (G609R) substitution at a conserved residue in the transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed that the mutation nearly eliminated the agonist-induced current. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31300657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 10-year-old boy (patient 5) with neurodevelopmental disorder with speech impairment and behavioral abnormalities (NEDLIB; <a href="/entry/618917">618917</a>), who had had a febrile convulsion at the age of 12 months, <a href="#24" class="mim-tip-reference" title="Salpietro, V., Dixon, C. L., Guo, H., Bello, O. D., Vandrovcova, J., Efthymiou, S., Maroofian, R., Heimer, G., Burglen, L., Valence, S., Torti, E., Hacke, M., and 80 others. <strong>AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.</strong> Nature Commun. 10: 3094, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31300657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31300657</a>] [<a href="https://doi.org/10.1038/s41467-019-10910-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31300657">Salpietro et al. (2019)</a> identified a de novo heterozygous c.905A-G transition (c.905A-G, NM_000826.3) in exon 7 of the GRIA2 gene, resulting in an asp302-to-gly (D302G) substitution at a conserved residue in the N-terminal domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed that the mutation nearly eliminated the agonist-induced current. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31300657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1735294501 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1735294501;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1735294501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1735294501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001195083" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001195083" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001195083</a>
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<p>In a 9-year-old boy (patient 9) with neurodevelopmental disorder with speech impairment and behavioral abnormalities (NEDLIB; <a href="/entry/618917">618917</a>), <a href="#24" class="mim-tip-reference" title="Salpietro, V., Dixon, C. L., Guo, H., Bello, O. D., Vandrovcova, J., Efthymiou, S., Maroofian, R., Heimer, G., Burglen, L., Valence, S., Torti, E., Hacke, M., and 80 others. <strong>AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.</strong> Nature Commun. 10: 3094, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31300657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31300657</a>] [<a href="https://doi.org/10.1038/s41467-019-10910-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31300657">Salpietro et al. (2019)</a> identified a de novo heterozygous c.1582C-A transversion (c.1582C-A, NM_000826.3) in exon 11 of the GRIA2 gene, resulting in a pro528-to-thr (P528T) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed that the mutation did not significantly affect the current amplitude. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31300657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 NEURODEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND BEHAVIORAL ABNORMALITIES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1579377564 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1579377564;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1579377564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1579377564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000986116 OR RCV001195084" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000986116, RCV001195084" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000986116...</a>
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<p>In 2 unrelated infants (patients 17 and 20) who died at 3 and 5 months of age, respectively (NEDLIB; <a href="/entry/618917">618917</a>), <a href="#24" class="mim-tip-reference" title="Salpietro, V., Dixon, C. L., Guo, H., Bello, O. D., Vandrovcova, J., Efthymiou, S., Maroofian, R., Heimer, G., Burglen, L., Valence, S., Torti, E., Hacke, M., and 80 others. <strong>AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.</strong> Nature Commun. 10: 3094, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31300657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31300657</a>] [<a href="https://doi.org/10.1038/s41467-019-10910-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31300657">Salpietro et al. (2019)</a> identified a de novo heterozygous c.1915G-T transversion (c.1915G-T, NM_000826.3) in exon 12 of the GRIA2 gene, resulting in an ala639-to-ser (A639S) substitution at a conserved residue adjacent to the transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed that the mutation reduced agonist-induced current amplitude and resulted in decreased cell-surface expression of GRIA2. Both infants had had uncontrolled seizures from the first days of life and never attained any motor or developmental milestones. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31300657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 NEURODEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND BEHAVIORAL ABNORMALITIES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs765072736 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs765072736;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs765072736?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs765072736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs765072736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001195085" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001195085" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001195085</a>
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<p>In 4 patients (16, 18, 21, and 24) with neurodevelopmental disorder with language impairment and behavioral abnormalities (NEDLIB; <a href="/entry/618917">618917</a>), <a href="#24" class="mim-tip-reference" title="Salpietro, V., Dixon, C. L., Guo, H., Bello, O. D., Vandrovcova, J., Efthymiou, S., Maroofian, R., Heimer, G., Burglen, L., Valence, S., Torti, E., Hacke, M., and 80 others. <strong>AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.</strong> Nature Commun. 10: 3094, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31300657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31300657</a>] [<a href="https://doi.org/10.1038/s41467-019-10910-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31300657">Salpietro et al. (2019)</a> identified a de novo heterozygous c.1939G-C transversion (c.1939G-C, NM_000826.3) in exon 12 of the GRIA2 gene, resulting in a val647-to-leu (V647L) substitution at a conserved residue in the M3-S2 linker domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed that the mutation did not significantly affect the current amplitude. All of these patients had seizures of various types and were noted to be nonverbal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31300657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>REFERENCES</strong>
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Armstrong, N., Gouaux, E.
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<strong>Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core.</strong>
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Neuron 28: 165-181, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11086992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11086992</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11086992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(00)00094-5" target="_blank">Full Text</a>]
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Biou, V., Bhattacharyya, S., Malenka, R. C.
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<strong>Endocytosis and recycling of AMPA receptors lacking GluR2/3.</strong>
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[<a href="https://doi.org/10.1073/pnas.0711412105" target="_blank">Full Text</a>]
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Brusa, R., Zimmermann, F., Koh, D.-S., Feldmeyer, D., Gass, P., Seeburg, P. H., Sprengel, R.
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<strong>Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice.</strong>
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Science 270: 1677-1680, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7502080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7502080</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7502080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.270.5242.1677" target="_blank">Full Text</a>]
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Chen, L., Durr, K. L., Gouaux, E.
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<strong>X-ray structures of AMPA receptor-cone snail toxin complexes illuminate activation mechanism.</strong>
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Science 345: 1021-1026, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25103405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25103405</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25103405[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25103405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1258409" target="_blank">Full Text</a>]
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Christie, L. A., Russell, T. A., Xu, J., Wood, L., Shepherd, G. M. G., Contractor, A.
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<strong>AMPA receptor desensitization mutation results in severe developmental phenotypes and early postnatal lethality.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20439731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20439731</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20439731[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20439731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0908206107" target="_blank">Full Text</a>]
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Chung, H. J., Steinberg, J. P., Huganir, R. L., Linden, D. J.
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<strong>Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12805550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12805550</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12805550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1082915" target="_blank">Full Text</a>]
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<a id="Conrad2008" class="mim-anchor"></a>
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Conrad, K. L., Tseng, K. Y., Uejima, J. L., Reimers, J. M., Heng, L.-J., Shaham, Y., Marinelli, M., Wolf, M. E.
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<strong>Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving.</strong>
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Nature 454: 118-121, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31300657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31300657</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31300657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41467-019-10910-w" target="_blank">Full Text</a>]
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</p>
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<a id="25" class="mim-anchor"></a>
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<a id="Sobolevsky2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sobolevsky, A. I., Rosconi, M. P., Gouaux, E.
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<strong>X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.</strong>
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Nature 462: 745-756, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19946266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19946266</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19946266[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19946266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature08624" target="_blank">Full Text</a>]
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<a id="26" class="mim-anchor"></a>
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<a id="Sommer1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sommer, B., Keinanen, K., Verdoorn, T. A., Wisden, W., Burnashev, N., Herb, A., Kohler, M., Takagi, T., Sakmann, B., Seeburg, P. H.
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<strong>Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1699275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1699275</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1699275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1699275" target="_blank">Full Text</a>]
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<a id="27" class="mim-anchor"></a>
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<a id="Steinberg2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Steinberg, J. P., Takamiya, K., Shen, Y., Xia, J., Rubio, M. E., Yu, S., Jin, W., Thomas, G. M., Linden, D. J., Huganir, R. L.
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<strong>Targeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16543133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16543133</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16543133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2006.02.025" target="_blank">Full Text</a>]
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<a id="28" class="mim-anchor"></a>
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<a id="Stumpf2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 06/24/2020.
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<a id="Sun1992" class="mim-anchor"></a>
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<div class="">
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<strong>Molecular cloning, chromosomal mapping, and functional expression of human brain glutamate receptors.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1311100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1311100</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1311100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.89.4.1443" target="_blank">Full Text</a>]
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<a id="Sun2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sun, Y., Olson, R., Horning, M., Armstrong, N., Mayer, M., Gouaux, E.
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<strong>Mechanism of glutamate receptor desensitization.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12015593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12015593</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12015593" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/417245a" target="_blank">Full Text</a>]
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<a id="Sutton2003" class="mim-anchor"></a>
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Sutton, M. A., Schmidt, E. F., Choi, K.-H., Schad, C. A., Whisler, K., Simmons, D., Karanian, D. A., Monteggia, L. M., Neve, R. L., Self, D. W.
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<strong>Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour.</strong>
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Nature 421: 70-75, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12511956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12511956</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12511956" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature01249" target="_blank">Full Text</a>]
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<a id="32" class="mim-anchor"></a>
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<a id="Tateno2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tateno, M., Sadakata, H., Tanaka, M., Itohara, S., Shin, R.-M., Miura, M., Masuda, M., Aosaki, T., Urushitani, M., Misawa, H., Takahashi, R.
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<strong>Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model.</strong>
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Hum. Molec. Genet. 13: 2183-2196, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15294873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15294873</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15294873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh246" target="_blank">Full Text</a>]
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<a id="33" class="mim-anchor"></a>
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<a id="Yelshanskaya2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yelshanskaya, M. V., Li, M., Sobolevsky, A. I.
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<strong>Structure of an agonist-bound ionotropic glutamate receptor.</strong>
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Science 345: 1070-1074, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25103407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25103407</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25103407[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25103407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1256508" target="_blank">Full Text</a>]
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<a id="34" class="mim-anchor"></a>
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<a id="Zhao2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhao, Y., Chen, S., Swensen, A. C., Qian, W. J., Gouaux, E.
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<strong>Architecture and subunit arrangement of native AMPA receptors elucidated by cryo-EM.</strong>
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Science 364: 355-362, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30975770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30975770</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30975770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aaw8250" target="_blank">Full Text</a>]
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</ol>
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<br />
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 06/25/2020
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</span>
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 06/18/2020<br>Ada Hamosh - updated : 10/14/2019<br>Ada Hamosh - updated : 9/29/2014<br>Patricia A. Hartz - updated : 8/1/2011<br>Cassandra L. Kniffin - updated : 2/15/2011<br>Cassandra L. Kniffin - updated : 1/19/2010<br>Ada Hamosh - updated : 1/8/2010<br>Ada Hamosh - updated : 9/11/2008<br>Patricia A. Hartz - updated : 3/13/2008<br>Ada Hamosh - updated : 8/13/2007<br>George E. Tiller - updated : 4/5/2007<br>Patricia A. Hartz - updated : 3/7/2006<br>Patricia A. Hartz - updated : 2/8/2006<br>Patricia A. Hartz - updated : 6/13/2005<br>Ada Hamosh - updated : 3/8/2004<br>Ada Hamosh - updated : 8/26/2003<br>Ada Hamosh - updated : 6/17/2003<br>Ada Hamosh - updated : 2/3/2003<br>Dawn Watkins-Chow - updated : 12/16/2002<br>Ada Hamosh - updated : 5/29/2002<br>Ada Hamosh - updated : 1/11/2001
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/8/1992
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 06/25/2020
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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alopez : 06/24/2020<br>ckniffin : 06/18/2020<br>alopez : 10/14/2019<br>alopez : 02/10/2015<br>alopez : 9/29/2014<br>mgross : 8/26/2011<br>terry : 8/1/2011<br>wwang : 3/9/2011<br>ckniffin : 2/15/2011<br>wwang : 1/27/2010<br>ckniffin : 1/19/2010<br>alopez : 1/11/2010<br>terry : 1/8/2010<br>alopez : 9/11/2008<br>mgross : 3/19/2008<br>terry : 3/13/2008<br>carol : 8/14/2007<br>terry : 8/13/2007<br>alopez : 4/11/2007<br>terry : 4/5/2007<br>mgross : 3/7/2006<br>wwang : 2/14/2006<br>terry : 2/8/2006<br>wwang : 6/30/2005<br>wwang : 6/24/2005<br>terry : 6/13/2005<br>wwang : 5/9/2005<br>terry : 4/29/2005<br>tkritzer : 3/9/2004<br>terry : 3/8/2004<br>alopez : 8/26/2003<br>terry : 8/26/2003<br>alopez : 6/17/2003<br>terry : 6/17/2003<br>alopez : 2/4/2003<br>terry : 2/3/2003<br>carol : 2/3/2003<br>tkritzer : 12/16/2002<br>tkritzer : 12/16/2002<br>alopez : 5/30/2002<br>terry : 5/29/2002<br>mgross : 1/12/2001<br>terry : 1/11/2001<br>dkim : 7/21/1998<br>mark : 2/23/1997<br>terry : 2/6/1996<br>mark : 12/7/1995<br>terry : 12/7/1995<br>terry : 12/7/1995<br>terry : 12/7/1995<br>carol : 3/2/1995<br>carol : 5/25/1993<br>carol : 4/7/1993<br>carol : 10/20/1992<br>carol : 9/9/1992<br>carol : 6/8/1992
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 138247
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<div>
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<h3>
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<span class="mim-font">
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GLUTAMATE RECEPTOR, IONOTROPIC, AMPA 2; GRIA2
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</span>
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</h3>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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GLUTAMATE RECEPTOR 2; GLUR2<br />
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GLURB
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GRIA2</em></strong>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 4q32.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 4:157,220,120-157,366,075 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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4q32.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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Neurodevelopmental disorder with language impairment and behavioral abnormalities
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</span>
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</td>
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<td>
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<span class="mim-font">
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618917
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Glutamate receptors sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) are ligand-activated cation channels that mediate the fast component of excitatory postsynaptic currents in neurons of the central nervous system. These channels are assembled from 4 related subunits, GLURA (GRIA1; 138248), GLURB (GRIA2), GLURC (GRIA3; 305915), GLURD (GRIA4; 138246), with the GLURB subunit rendering the channel almost impermeable to Ca(2+) (Hollmann et al., 1991). </p>
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By PCR of a human brain cDNA library using primers based on rat glutamate receptors, Sun et al. (1992) obtained a partial cDNA corresponding to approximately two-thirds of the coding region of a receptor homologous to rat brain Glur2. </p><p>The C-terminal halves of the GLUR channels contain 4 transmembrane regions. Sommer et al. (1990) determined that a small segment preceding the fourth transmembrane region in each GLUR channel subunit exists in 2 versions that have different amino acid sequences. These modules, designated 'flip' and 'flop,' are encoded by adjacent exons. About half of the GLUR cDNAs isolated from rat brain libraries specified the flip sequence, and the other half specified the flop sequence. Within rat brain, the flip versions of GLURA, GLURB, and GLURC were detected in CA3 neurons of the hippocampus, while both versions of these receptors and GLURD were found in CA1 neurons. Other central nervous system regions showed differential expression of flip and flop modules for each of the GLUR genes. </p><p>Using in situ hybridization, McLaughlin et al. (1993) found that expression of GLURA and GLURB in human hippocampus differed from their expression in rat hippocampus. In human, both genes were preferentially expressed in the dentate gyrus and CA1 regions, with lower expression in CA3. An exception was GLURB flop, which showed lower expression in CA3 than in dentate gyrus. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Sommer et al. (1990) determined that the flip and flop versions of the rat GLUR genes impart different pharmacologic and kinetic properties on currents evoked by L-glutamate or AMPA, but they do not differ in their response to kainate. The authors concluded that the exon switching may underlie adaptive changes in neurons such as synaptic plasticity. </p><p>Paschen et al. (1994) demonstrated RNA editing, posttranscriptional change of the sequence at the mRNA level, in human GLUR2 and GLUR6 (GRIK2; 138244), as had previously been demonstrated in rats. A CAG, coding for glutamine within the putative second transmembrane domain of GLUR2, is changed to CGG, coding for arginine in the mRNA sequence. As in the rat, the GLUR2 subunit mRNA is completely edited in human brain. However, GLUR6 is only 10% edited in the corpus callosum and 90% edited in the gray matter. </p><p>In rat hippocampal pyramidal neurons, Daw et al. (2000) demonstrated that interruption of the interaction between C-terminal Glur2 and PDZ domain-containing proteins, such as GRIP (603597) and PICK1 (605926), resulted in increased AMPA receptor-mediated excitatory transmission and blockade of long-term depression. Inhibition of protein kinase C (PKC; see 176960) prevented these effects. Daw et al. (2000) proposed a model in which the maintenance of long-term depression involves the binding of AMPA receptors, via the Glur2 subunit, to PDZ proteins to prevent their reinsertion, and that protein kinase C plays a role in receptor insertion. </p><p>By analyzing subcellular distribution and endoplasmic reticulum (ER) export kinetics, Greger et al. (2002) showed that, unlike GluR1, GluR2 remains partly in an intracellular pool in the ER and is extensively complexed with GluR3 in rat brain. Using mutagenesis, Greger et al. (2002) showed that elements in the C terminus of GluR2, including the PDZ motif, are required for GluR2 forward-transport from the ER. The authors found that ER retention of GluR2 was controlled by arg607 (R607) at the Q/R editing site. Reversion of this residue to gln (R607Q), as is found in GluR1, resulted in GluR1-like rapid release from the ER pool and elevated surface expression of GluR2 in neurons. Greger et al. (2002) concluded that the arg607 residue of GluR2 controls exit from the ER and may thereby ensure the availability of GluR2 for assembly into AMPA receptors. </p><p>Cerebellar long-term depression is a model of synaptic memory that requires protein kinase C (PKC) activation and is expressed as a reduction in the number of postsynaptic AMPA receptors (AMPARs). Chung et al. (2003) found that long-term depression was absent in cultured cerebellar Purkinje cells from mutant mice lacking the AMPAR GluR2 subunit and could be rescued by transient transfection with the wildtype GluR2 subunit. Transfection with GluR2 carrying a point mutation that eliminated PKC phosphorylation of ser880 in the carboxy-terminal PDZ ligand of GluR2 failed to restore long-term depression. In contrast, transfection with GluR2 carrying a point mutation that mimicked phosphorylation at ser880 occluded subsequent long-term depression. Thus, PKC phosphorylation of GluR2 on ser880 is a critical event in the induction of cerebellar long-term depression. </p><p>The abundance of postsynaptic AMPARs correlates with the size of the synapse and the dimensions of the dendritic spine head. Moreover, long-term potentiation is associated with formation of dendritic spines as well as synaptic delivery of AMPARs. Passafaro et al. (2003) demonstrated that overexpression of GLUR2 increases dendritic spine size and density in hippocampal neurons, and more remarkably, induces spine formation in GABA-releasing interneurons that normally lack spines. The extracellular N-terminal domain of GLUR2 is responsible for this effect, and heterologous fusion proteins of the N-terminal domain of GLUR2 inhibit spine morphogenesis. Passafaro et al. (2003) proposed that the N-terminal domain of GLUR2 functions at the cell surface as part of a receptor-ligand interaction that is important for spine growth and/or stability. </p><p>Sutton et al. (2003) demonstrated that extinction training during the withdrawal from chronic cocaine self-administration in rats induces experience-dependent increases in the GLUR1 and GLUR2/3 subunits of AMPA glutamate receptors in the nucleus accumbens shell, a brain region that is critically involved in cocaine reward. Increases in the GLUR1 subunit were positively associated with a level of extinction achieved during training, suggesting that GLUR1 may promote extinction of cocaine seeking. Sutton et al. (2003) showed that viral-mediated overexpression of both GLUR1 and GLUR2 in nucleus accumbens shell neurons facilitates extinction of cocaine- but not sucrose-seeking responses. A single extinction training session, when conducted during GLUR subunit overexpression, attenuated stress-induced relapse to cocaine seeking even after GLUR overexpression declined. Sutton et al. (2003) concluded that extinction-induced plasticity in AMPARs may facilitate control over cocaine seeking by restoring glutamatergic tone in the nucleus accumbens, and may reduce the propensity for relapse under stressful situations in prolonged abstinence. </p><p>Kawahara et al. (2004) extracted RNA from single motor neurons isolated with a laser microdissector from 5 individuals with sporadic amyotrophic lateral sclerosis (ALS1; 105400) and 5 normal control subjects. GluR2 RNA editing was 100% efficient in the control samples, but the editing efficiency varied between 0 and 100% in the motor neurons from each individual with ALS and was incomplete in 44 of them (56%). Mice transgenic for GluR2 made artificially permeable to calcium ions developed motor neuron disease late in life (Feldmeyer et al., 1999), indicating that motor neurons may be specifically vulnerable to defective RNA editing. Kawahara et al. (2004) suggested that defective GluR2 RNA editing at the Q/R site may be relevant to ALS etiology. </p><p>Phosphorylation of GluR1 (GRIA1; 138248) by CaMKII (see CAMK2A; 114078) increases conductance of homodimeric GluR1 channels. In rat, Oh and Derkach (2005) found that incorporation of GluR2 in GluR1/GluR2 heterodimers disrupted the coupling between GluR1 phosphorylation and channel conductance, keeping the GluR1/GluR2 heteromers in low conductance state regardless of GluR1 phosphorylation. </p><p>At rat cerebellar parallel fiber-stellate cell synapses, Ca(2+) influx through Glur2-lacking AMPARs drives incorporation of Ca(2+)-impermeable Glur2-containing AMPARs, generating rapid changes in excitatory postsynaptic current properties. Liu and Cull-Candy (2005) found that repetitive synaptic activity triggered loss of Glur2-lacking AMPARs by disrupting their interaction with Grip (GRIP1; 604597). Pick (PICK1; 605926) drove activity-dependent delivery of Glur2-containing AMPARs into the synaptic membrane. Liu and Cull-Candy (2005) concluded that dynamic regulation of AMPARs by GRIP and PICK provides a mechanism for controlling Ca(2+) permeability of synaptic receptors. </p><p>Metabotropic glutamate receptor (see 604099)-dependent long-term depression in the ventral tegmental area efficiently reverses cocaine-induced strengthening of excitatory inputs onto dopamine neurons. Mameli et al. (2007) showed that metabotropic glutamate receptor long-term depression is expressed by an exchange of GluR2-lacking AMPA receptors for GluR2-containing receptors with a lower single-channel conductance. The synaptic insertion of GluR2 depends on de novo protein synthesis via rapid mRNA translation of GluR2. Mameli et al. (2007) concluded that regulated synthesis of GluR2 in the ventral tegmental area is required to reverse cocaine-induced synaptic plasticity. </p><p>Panicker et al. (2008) found that the C terminus of mouse Glur2 was not required for Glur2 synaptic insertion. </p><p>Biou et al. (2008) found that AMPA receptors lacking Glur2 and Glur3 were permeable to calcium and that this permeability influenced the subcellular sites in cultured mouse hippocampal neurons at which activity-dependent AMPA receptor endocytosis occurred. </p><p>Panicker et al. (2008) and Biou et al. (2008) noted that RNA editing resulting in a switch of Q607 to R607 in GLUR2 controls the assembly of GLUR2-containing AMPA receptors and makes them impermeable to calcium and resistant to block by polyamines. </p><p>Conrad et al. (2008) showed that the number of synaptic AMPA receptors in the accumbens is increased after prolonged withdrawal from cocaine self-administration by the addition of new AMPA receptors lacking GluR2. Furthermore, they showed that these new receptors mediate the incubation of cocaine craving. The results indicate that GluR2-lacking AMPA receptors could be a new target for drug development for the treatment of cocaine addiction. Conrad et al. (2008) proposed that after prolonged withdrawal from cocaine, increased numbers of synaptic AMPA receptors combined with the higher conductance of GluR2-lacking AMPA receptors causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Armstrong and Gouaux (2000) determined the crystal structures of the GLUR2 ligand-binding core in the apo state and in the presence of the antagonist DNQX, the partial agonist kainate, and the full agonists AMPA and glutamate. </p><p>Sobolevsky et al. (2009) reported the crystal structure of the rat GluA2 receptor at 3.6-angstrom resolution in complex with a competitive antagonist. The receptor harbors an overall axis of 2-fold symmetry with the extracellular domains organized as pairs of local dimers and with the ion channel domain exhibiting 4-fold symmetry. </p><p>Chen et al. (2014) determined multiple x-ray crystal structures of the GluA2 AMPA receptor in complex with a Conus striatus cone snail toxin, a positive allosteric modulator, and orthosteric agonists, at 3.8- to 4.1-angstrom resolution. The authors showed how the toxin acts like a straitjacket on the ligand-binding domain (LBD) 'gating ring,' restraining the domains via both intra- and interdimer crosslinks such that agonist-induced closure of the LBD 'clamshells' is transduced into an iris-like expansion of the gating ring. By structural analysis of activation-enhancing mutants, Chen et al. (2014) showed how the expansion of the LBD gating ring results in pulling forces on the M3 helices that, in turn, are coupled to ion channel gating. </p><p>Yelshanskaya et al. (2014) reported a structure of a homotetrameric rat GluA2 receptor in complex with partial agonist (S)-5-nitrowillardiine. Comparison of this structure with the closed-state structure in complex with competitive antagonist ZK 200775 suggested conformational changes that occur during ionotropic glutamate receptor (iGluR) gating. Guided by the structures, Yelshanskaya et al. (2014) engineered disulfide crosslinks to probe domain interactions that are important for iGluR gating events. </p><p>Sun et al. (2002) demonstrated a mechanism of desensitization of AMPA glutamate receptors. Using the GluR2 AMPA-sensitive glutamate receptor, Sun et al. (2002) showed that the ligand-binding cores form dimers and that stabilization of the intradimer interface by either mutations or allosteric modulators reduces desensitization. Perturbations that destabilize the interface enhance desensitization. Receptor activation involves conformational changes within each subunit that result in an increase in the separation of portions of the receptor that are linked to the ion channel. Sun et al. (2002) concluded that their analysis defines the dimer interface in the resting and activated state, indicates how ligand binding is coupled to gating, and suggests modes of dimer-dimer interaction in the assembled tetramer. Desensitization occurs through rearrangement of the dimer interface, which disengages the agonist-induced conformational change in the ligand-binding core from the ion channel gate. </p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Herguedas et al. (2019) presented a cryoelectron microscopy structure of the heteromeric GluA1 (138248)/GluA2 receptor associated with 2 transmembrane AMPAR regulatory protein (TARP) gamma-8 (606900) auxiliary subunits, the principal AMPAR complex at hippocampal synapses. Within the receptor, the core subunits arrange to give the GluA2 subunit dominant control of gating. This structure revealed the geometry of the Q/R site that controls calcium flux, suggested association of TARP-stabilized lipids, and demonstrated that the extracellular loop of gamma-8 modulates gating by selectively interacting with the GluA2 ligand-binding domain. </p><p>Zhao et al. (2019) elucidated the structures of 10 distinct native AMPA receptor complexes by single-particle cryoelectron microscopy and found that receptor subunits are arranged nonstochastically, with the GluA2 subunit preferentially occupying the B and D positions of the tetramer and with triheteromeric assemblies comprising a major population of native AMPA receptors. GluA1 predominantly accesses the A or C positions. Cryo-EM maps define the structure for S2-M4 linkers between the ligand-binding and transmembrane domains, suggesting how neurotransmitter binding is coupled to ion channel gating. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By PCR analysis of somatic cell hybrid cell lines, Sun et al. (1992) assigned the GLUR2 gene to chromosome 4. Use of a panel of 7 additional cell hybrids containing various deletions of chromosome 4 permitted sublocalization to 4q25-q34.3. A pseudogene or related gene appeared to be situated on chromosome 8. McNamara et al. (1992) narrowed the assignment to 4q32-q33 by fluorescence in situ suppression hybridization. </p><p>Stumpf (2020) mapped the GRIA2 gene to chromosome 4q32.1 based on an alignment of the GRIA2 sequence (GenBank BC010574) with the genomic sequence (GRCh38).</p><p>Using PCR with a panel of DNA from an interspecific backcross, and through RFLV and haplotype analyses, Gregor et al. (1993) mapped the Glur2 gene in the mouse to a region of chromosome 3 that contains the 'spastic' mutation. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>In 25 unrelated patients with neurodevelopmental disorder with language impairment and behavioral abnormalities (NEDLIB; 618917), Salpietro et al. (2019) identified de novo heterozygous mutations in the GRIA2 gene (see, e.g., 138247.0001-138247.0006). There were 15 missense, 2 splice site, and 1 nonsense mutation, 1 in-frame deletion, and 2 frameshift variants; mutations occurred throughout the gene. The mutations, which were found by whole-genome, whole-exome, or targeted sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed variable effects of the mutations. Seven of 11 mutations caused a decreased agonist-induced current compared to wildtype, 3 mutations had normal current amplitudes, and 1 resulted in an increase in current amplitude. When coexpressed with GRIA1 (138248), most of the mutant proteins showed a decreased current amplitude compared to wildtype, and some affected rectification. Some mutations reduced the GRIA2 surface expression, suggesting that defects in heteromerization or cell surface trafficking may be another important pathogenic mechanism. Overall, most of the mutations appeared to result in a loss of function. No clear genotype/phenotype correlations emerged, although 2 patients who died in infancy both carried the same variant (A639S; 138247.0005). Salpietro et al. (2019) emphasized the biologic diversity of the tested mutants, and suggested that phenotypic differences may arise from different effects of distinct mutations. The report implicated GRIA2 dysfunction and disruption of glutamatergic synaptic transmission in neurodevelopmental disorders. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The molecular determinant of the dominant property of the GLURB subunit in rendering the AMPA-sensitive channels impermeable to calcium can be traced to the arginine residue at position 586 of the mature subunit, which lies within the pore-forming segment M2. This arginine is not gene encoded but is posttranscriptionally introduced into GLURB pre-mRNA by site-selective adenosine deamination, which leads to the change of a CAA glutamine (Q) codon to a codon for arginine (R) in more than 99% of mRNA molecules. Termed Q/R site editing, this nuclear process depends on a double-stranded RNA structure formed in the pre-mRNA by the editing site in exon 11 and the editing site complementary sequence (ECS) in intron 11 (Kohler et al., 1994). To investigate in an animal model the relevance of this process for central nervous system physiology, Brusa et al. (1995) targeted intron 11 of the Glur2 gene in mouse ES cells for replacement of the ECS element, and then injected correctly engineered cells into C57BL/6 blastocysts. One of several resultant chimeric animals showed vertical transmission of the knockout allele in a mendelian fashion, indicating that the allele did not adversely affect embryonic development. Heterozygous mice synthesized unedited GLURB subunits and, in principal neurons and interneurons, expressed AMPA receptors with increased calcium permeability. These mice developed seizures and died by 3 weeks of age, suggesting to Brusa et al. (1995) that GLURB pre-mRNA editing is essential for brain function. </p><p>Amyotrophic lateral sclerosis (ALS; see 105400) is a neurodegenerative disorder characterized by cell death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. Approximately 15 to 20% of cases of familial ALS are associated with mutations in the superoxide dismutase-1 gene, SOD1 (147450). To evaluate the contribution of motoneuronal Ca(2+)-permeable (GluR2 subunit-lacking) alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors to SOD1-related motoneuronal death, Tateno et al. (2004) generated choline acetyltransferase (ChAT; 118490)-GluR2 transgenic mice with significantly reduced Ca(2)+ permeability of these receptors in spinal motoneurons. Crossbreeding of the Sod1(G93A) transgenic mouse model of ALS with ChAT-GluR2 mice led to marked delay of disease onset, mortality, and the pathologic hallmarks such as release of cytochrome c from mitochondria, induction of cox2 (600262), and astrogliosis. Subcellular fractionation analysis revealed that unusual SOD1 species accumulated in 2 fractions (P1, composed of nuclei and certain kinds of cytoskeletons such as neurofilaments and glial fibrillary acidic protein (GFAP; 137780), and P2, composed of mitochondria) long before disease onset and then extensively accumulated in the P1 fractions by disease onset. All these processes for unusual SOD1 accumulation were considerably delayed by GluR2 overexpression. Ca(2+) influx through atypical motoneuronal AMPA receptors thus promoted a misfolding of mutant SOD1 protein and eventual death of these neurons. </p><p>Steinberg et al. (2006) generated 2 lines of transgenic mice: Pick1 (605926)-null mice and those with targeted disruption of the C-terminal PDZ ligand of GluR2, which is a binding site of GluR2 to Pick1. Purkinje cells and cerebellar slices from both groups of mutant mice showed absence of cerebellar long-term depression (LTD). Rescue studies showed that the PDZ and the BAR domains of Pick1 were required for LTD. Phosphorylation at ser880 of GluR2 was also required for cerebellar LTD, as well as for proper GluR2 trafficking. Overall, the results indicated that Pick1-GluR2 PDZ-based interactions and GluR2 phosphorylation are required for cerebellar LTD expression in mice. </p><p>Postsynaptic AMPA receptor desensitization plays a major role in depression at synapses in which glutamate remains in the synaptic cleft for prolonged periods of time during normal operation of the synapse. Christie et al. (2010) found that homozygous expression of a nondesensitizing point mutation, leu483 to tyr (L483Y), in the mouse Gria2 receptor subunit was embryonic lethal. Heterozygous mutant mice were initially viable, but they developed a severe neurologic and developmental phenotype that included significant runting, abnormal gait, progressively severe seizures, and mortality in the third postnatal week. Western blot and immunohistochemical analyses revealed drastic compensatory changes in glutamate receptor expression and reduced extrasynaptic AMPA receptor density in mutant mice. Christie et al. (2010) concluded that AMPA receptor desensitization is critical for viability and function of the central nervous system. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>6 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 NEURODEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND BEHAVIORAL ABNORMALITIES</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRIA2, ASP611ASN
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<br />
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SNP: rs1553956958,
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ClinVar: RCV000509467, RCV001195080
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 19-year-old man (patient 3) with neurodevelopmental disorder with language impairment and behavioral abnormalities (NEDLIB; 618917), who had developmental regression starting in late childhood, Salpietro et al. (2019) identified a de novo heterozygous c.1831G-A transition (c.1831G-A, NM_000826.3) in exon 11 of the GRIA2 gene, resulting in an asp611-to-asn (D611N) substitution at a conserved residue in the transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed that the mutation did not significantly affect the current amplitude. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0002 NEURODEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND BEHAVIORAL ABNORMALITIES</strong>
|
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</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRIA2, GLY609ARG
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<br />
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SNP: rs1735303754,
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ClinVar: RCV001195081
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a 19-year-old woman (patient 4) with neurodevelopmental disorder with language impairment and behavioral abnormalities (NEDLIB; 618917), who had a history of developmental regression, Salpietro et al. (2019) identified a de novo heterozygous c.1825G-A transition (c.1825G-A, NM_000826.3) in exon 11 of the GRIA2 gene, resulting in a gly609-to-arg (G609R) substitution at a conserved residue in the transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed that the mutation nearly eliminated the agonist-induced current. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0003 NEURODEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND BEHAVIORAL ABNORMALITIES</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRIA2, ASP302GLY
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<br />
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SNP: rs1735116193,
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ClinVar: RCV001195082
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a 10-year-old boy (patient 5) with neurodevelopmental disorder with speech impairment and behavioral abnormalities (NEDLIB; 618917), who had had a febrile convulsion at the age of 12 months, Salpietro et al. (2019) identified a de novo heterozygous c.905A-G transition (c.905A-G, NM_000826.3) in exon 7 of the GRIA2 gene, resulting in an asp302-to-gly (D302G) substitution at a conserved residue in the N-terminal domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed that the mutation nearly eliminated the agonist-induced current. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 NEURODEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND BEHAVIORAL ABNORMALITIES</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRIA2, PRO528THR
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<br />
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SNP: rs1735294501,
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ClinVar: RCV001195083
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 9-year-old boy (patient 9) with neurodevelopmental disorder with speech impairment and behavioral abnormalities (NEDLIB; 618917), Salpietro et al. (2019) identified a de novo heterozygous c.1582C-A transversion (c.1582C-A, NM_000826.3) in exon 11 of the GRIA2 gene, resulting in a pro528-to-thr (P528T) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed that the mutation did not significantly affect the current amplitude. </p>
|
|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 NEURODEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND BEHAVIORAL ABNORMALITIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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GRIA2, ASN639SER
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<br />
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SNP: rs1579377564,
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ClinVar: RCV000986116, RCV001195084
|
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</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 unrelated infants (patients 17 and 20) who died at 3 and 5 months of age, respectively (NEDLIB; 618917), Salpietro et al. (2019) identified a de novo heterozygous c.1915G-T transversion (c.1915G-T, NM_000826.3) in exon 12 of the GRIA2 gene, resulting in an ala639-to-ser (A639S) substitution at a conserved residue adjacent to the transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed that the mutation reduced agonist-induced current amplitude and resulted in decreased cell-surface expression of GRIA2. Both infants had had uncontrolled seizures from the first days of life and never attained any motor or developmental milestones. </p>
|
|
</span>
|
|
</div>
|
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 NEURODEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND BEHAVIORAL ABNORMALITIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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GRIA2, VAL647LEU
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<br />
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SNP: rs765072736,
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|
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gnomAD: rs765072736,
|
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ClinVar: RCV001195085
|
|
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</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 4 patients (16, 18, 21, and 24) with neurodevelopmental disorder with language impairment and behavioral abnormalities (NEDLIB; 618917), Salpietro et al. (2019) identified a de novo heterozygous c.1939G-C transversion (c.1939G-C, NM_000826.3) in exon 12 of the GRIA2 gene, resulting in a val647-to-leu (V647L) substitution at a conserved residue in the M3-S2 linker domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies in transfected HEK293T cells showed that the mutation did not significantly affect the current amplitude. All of these patients had seizures of various types and were noted to be nonverbal. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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Armstrong, N., Gouaux, E.
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<p class="mim-text-font">
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Biou, V., Bhattacharyya, S., Malenka, R. C.
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<strong>Endocytosis and recycling of AMPA receptors lacking GluR2/3.</strong>
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Brusa, R., Zimmermann, F., Koh, D.-S., Feldmeyer, D., Gass, P., Seeburg, P. H., Sprengel, R.
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Chen, L., Durr, K. L., Gouaux, E.
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<strong>X-ray structures of AMPA receptor-cone snail toxin complexes illuminate activation mechanism.</strong>
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Christie, L. A., Russell, T. A., Xu, J., Wood, L., Shepherd, G. M. G., Contractor, A.
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Chung, H. J., Steinberg, J. P., Huganir, R. L., Linden, D. J.
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<strong>Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving.</strong>
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Nature 454: 118-121, 2008.
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Daw, M. I., Chittajallu, R., Bortolotto, Z. A., Dev, K. K., Duprat, F., Henley, J. M., Collingridge, G. L., Isaac, J. T. R.
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Feldmeyer, D., Kask, K., Brusa, R., Kornau, H.-C., Kolhekar, R., Rozov, A., Burnashev, N., Jensen, V., Hvalby, O., Sprengel, R., Seeburg, P. H.
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Hollmann, M., Hartley, M., Heinemann, S.
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Kawahara, Y., Ito, K., Sun, H., Aizawa, H., Kanazawa, I., Kwak, S.
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Kohler, M., Kornau, H. C., Seeburg, P. H.
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<strong>The organization of the gene for the functionally dominant alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit Glu4-B.</strong>
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Liu, S. J., Cull-Candy, S. G.
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<strong>Subunit interaction with PICK and GRIP controls Ca(2+) permeability of AMPARs at cerebellar synapses.</strong>
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Nature Neurosci. 8: 768-775, 2005.
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Mameli, M., Balland, B., Lujan, R., Luscher, C.
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<strong>Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area.</strong>
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Science 317: 530-533, 2007.
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McLaughlin, D. P., Cheetham, M. E., Kerwin, R. W.
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<strong>Expression of alternatively-spliced glutamate receptors in human hippocampus.</strong>
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[PubMed: 8420792]
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<li>
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<p class="mim-text-font">
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|
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