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<title>Cell lines expressing known and putative CNS-expressed Gs-coupled GPCRs for screening of compounds for translational focusing and drug discovery | NIH Research Festival</title>
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<article><div class="banner banner--gray banner--compact" style="--banner-background-image: url('/sites/default/files/media/image/2021-03/2015.jpg');--banner-background-focus: 50% 50%"><div class="banner__wrapper"><div class="banner__container"><h2 class="banner__heading">NIH Research Festival</h2><div class="banner__content"><p><strong><time datetime="2015-09-16">September 16</time> – <time datetime="2015-09-18">18, 2015</time></strong></p></div></div></div></div></article>
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<div class="section"><div data-drupal-messages-fallback class="hidden"></div></div><main role="main"><div id="main-content" tabindex="-1"></div><div class="section"><div class="content-sidebar"><div class="content-sidebar__main"><div class="content-sidebar__main-content"><div id="block-mainpagecontent-2"><article><h1>Cell lines expressing known and putative CNS-expressed Gs-coupled GPCRs for screening of compounds for translational focusing and drug discovery</h1><div class="schedule"><div class="schedule__label"><div class="schedule__label-text"><time datetime="2015-09-18">Friday, September 18, 2015</time>
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– Poster Session V
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</div></div><div class="schedule__content"><div class="schedule__item"><div class="schedule__time">2:00 – 3:30 p.m.</div><div class="schedule__description"><p><strong>FAES Terrace</strong></p></div><div class="schedule__description"><p><strong>NIMH</strong></p></div><div class="schedule__description"><p><strong>PHARM-5</strong></p></div></div></div></div><h2>Authors</h2><ul><li>AC Emery</li><li>M Ferrer</li><li>CD Westover</li><li>RA Alvarez</li><li>W Xu</li><li>SZ Jiang</li><li>LE Eiden</li><li>MV Eiden</li></ul><h2>Abstract</h2><p>G protein-coupled receptors (GPCRs) that engage Gs and activate adenylate cyclase exert effects on neuronal function by activating multiple cAMP sensors. Protein kinase A (PKA), and the guanine nucleotide exchange factors Epac2/Rapgef4 and neuritogenic cAMP sensor (NCS)/Rapgef2, in particular, mediate neuronal activation of CREB, p38, and ERK1/2, and cell survival, growth arrest, and neuritogenesis, respectively (Emery et al., J. Biol. Chem. 289:10126, 2014). Thus, drugs developed as agonists, antagonists, or biased agonists/antagonists for CNS Gs-coupled GPCRs are most usefully screened for translational focusing of known and orphan putative Gs-coupled GPCRs using assays that monitor not only cAMP elevation, but also the downstream activation of CREB, p38, and ERK1/2. The cAMP sensor NCS/Rapgef2 appears to be functionally expressed, and linked to ERK activation, only in neurons and neuroendocrine cell lines (Emery et al., Sci. Signaling 6(281), ra51, 2013). The neuroendocrine cell line NS-1 has been used to create sub-lines expressing ~30 of the 59 known and putative Gs-coupled GPCRs. Using high-content analysis, these lines have allowed the categorization of Gs-coupled GPCRs into those that do and do not activate NCS/Rapgef2, which has been linked to the action of various Gs-coupled GPCR ligands in the central nervous system, including PACAP, dopamine, and norepinephrine. This platform will facilitate assessment of the specificity and downstream functional activity of known Gs-GPCR-directed drugs, and potential pharmacological de-orphanization of CNS-expressed GPCRs of suspected importance in neuronal cellular signaling.</p><p><strong>Scientific Focus Area</strong>: Molecular Pharmacology</p><p class="updated"><small>This page was last updated on Friday, March 26, 2021</small></p></article>
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