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<p class="publishdate"><span property="dc:date" datatype="xsd:dateTime" content="2017-02-14T00:00:00-05:00" class="date-display-single">February 14, 2017</span></p><div class='syndicate'><h1>Protein structure reveals how LSD affects the brain</h1><div class="callout callout-with-border"><h3>At a Glance</h3>
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<ul>
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<li>Researchers determined the structure of LSD interacting with its target protein in the human brain, a receptor for the chemical messenger serotonin.</li>
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<li>Insights into the molecular mechanisms of LSD’s activity could lead to new avenues for future drug development.</li>
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<picture title="Structure of LSD and Receptor">
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-large/public/news-events/research-matters/2017/20170204-lsd.jpg?itok=l4NzQtoH&timestamp=1487012335 1x" media="screen and (min-width: 960px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2017/20170204-lsd.jpg?itok=DoNlLDVL&timestamp=1487012335 1x" media="screen and (min-width: 800px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium-small/public/news-events/research-matters/2017/20170204-lsd.jpg?itok=4lj0elB_&timestamp=1487012335 1x" media="screen and (min-width: 600px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-small/public/news-events/research-matters/2017/20170204-lsd.jpg?itok=s1uYtrr_&timestamp=1487012335 1x" media="screen and (min-width: 480px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-tiny/public/news-events/research-matters/2017/20170204-lsd.jpg?itok=5HgEA8AD&timestamp=1487012335 1x" media="screen and (min-width: 0)" />
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<img src="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2017/20170204-lsd.jpg?itok=DoNlLDVL&timestamp=1487012335" alt="Structure of LSD and Receptor" title="Structure of LSD and Receptor" />
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</picture><span class="caption">An artistic representation of LSD (in blue) fitting into a serotonin receptor (the white ribbon).</span><span class="credit">Bryan Roth</span></div>
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</div><p>Lysergic acid diethylamide, or LSD, can alter perception (awareness of surrounding objects and conditions), thoughts, and feelings. It can also cause hallucinations—sensations and images that seem real even though they’re not. These “trips” can last many hours, long after LSD has been cleared from the bloodstream.</p>
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<p>LSD was first synthesized in 1938, and its hallucinogenic effects discovered soon afterward. However, how the compound causes its effects in the brain hasn’t been well understood. LSD is a member of a class of drugs called ergolines, which are used to treat many conditions, including migraine headaches and Parkinson’s disease. Understanding how the compound exerts its unique effects could provide insights to guide the development of future therapeutics.</p>
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||
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||
<p>LSD interacts with proteins on the surface of brain cells called serotonin receptors. Serotonin is a chemical messenger that helps brain cells communicate. LSD appears to act through a particular receptor called 5-HT<sub>2A</sub>R. To gain insights into LSD’s effects, a research team led by Dr. Bryan Roth at the University of North Carolina crystallized a related receptor, 5-HT<sub>2B</sub>R, attached to LSD. The scientists used x-ray crystallography to visualize the structure. Their study was supported by NIH’s National Institute of Mental Health (NIMH). Results were published on January 26, 2017, in <em>Cell</em>.</p>
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||
<p>Serotonin receptors activate 2 major signaling pathways within cells: through G-proteins and through β-arrestins. The researchers found that LSD binds its receptor in a way that causes it to act mostly through the β-arrestin pathway instead of the G-protein pathway. Related ergoline compounds, the scientists found, differ in the way they structurally interact with the receptor. Further laboratory experiments and computer analyses revealed that these distinct but similar compounds can shape the structure of the receptor to trigger different effects.</p>
|
||
|
||
<p>The team also found that the serotonin receptor closes a “lid” over the LSD molecule, preventing it from quickly detaching. This likely explains the drug’s long-lasting effects. A mutant form of the receptor with a weaker lid had reduced β-arrestin pathway activity, while leaving G-protein pathway activity unaffected.</p>
|
||
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||
<p>“This study sheds light on the mechanism of psychoactive drug action, including how certain drugs activate one signaling pathway inside cells while avoiding another,” explains Dr. Laurie Nadler, chief of NIMH’s Neuropharmacology Program. “Taken together with other recent studies of drug-receptor complexes, this work provides proof-of-concept for the design of drugs with desired signaling properties and fewer undesired side-effects.”</p>
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<p>Roth and other colleagues <a href="https://www.nih.gov/news-events/nih-research-matters/designing-more-effective-opioids">recently showed</a> the potential of such structure-based design. Based on similar discoveries about an opioid receptor, they created a molecule that effectively alleviates pain in mice, but with fewer side effects than morphine.</p>
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</div><h2 class="label-above">Related Links</h2><ul class="spaced print-urls"><li><a href="https://www.nih.gov/news-events/nih-research-matters/designing-more-effective-opioids" target="_top">Designing More Effective Opioids</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/serotonin-transporter-structure-revealed" target="_top">Serotonin Transporter Structure Revealed</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/genes-help-predict-response-alcoholism-treatment" target="_top">Genes Help Predict Response to Alcoholism Treatment </a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/serotonin-helps-control-body-temperature-breathing" target="_top">Serotonin Helps Control Body Temperature and Breathing</a></li><li><a href="https://www.drugabuse.gov/drugs-abuse/hallucinogens" target="_top">Hallucinogens </a></li></ul><p class="footnote"><strong class="label-inline">References: </strong><a href="https://www.ncbi.nlm.nih.gov/pubmed/28129538">Crystal Structure of an LSD-Bound Human Serotonin Receptor.</a> Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, Lansu K, Schools ZL, Che T, Nichols DE, Shoichet BK, Dror RO, Roth BL. <em>Cell</em>. 2017 Jan 26;168(3):377-389.e12. doi: 10.1016/j.cell.2016.12.033. PMID: 28129538.</p><p class="footnote"><strong class="label-inline">Funding: </strong>NIH’s National Institute of Mental Health (NIMH) and the Michael Hooker Distinguished Chair of Pharmacology.</p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/research-context-can-we-slow-aging">Research in Context: Can we slow aging?</a></p>
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|
||
<p><a href="https://www.nih.gov/news-events/nih-research-matters/brain-changes-observed-during-pregnancy">Brain changes observed during pregnancy</a></p>
|
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|
||
<p><a href="https://www.nih.gov/news-events/nih-research-matters/research-context-detecting-cancer">Research in Context: Detecting cancer</a></p>
|
||
|
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/risk-future-burden-dementia-united-states">Risk and future burden of dementia in the United States </a></p>
|
||
|
||
<p><a href="https://www.nih.gov/news-events/nih-research-matters/complete-wiring-map-adult-fruit-fly-brain">Complete wiring map of an adult fruit fly brain</a></p>
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<h3 class="block__title">About NIH Research Matters</h3>
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<p><strong>Editor:</strong> Harrison Wein, Ph.D.</p>
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<p><strong>Assistant Editors:</strong> Vicki Contie and Brian Doctrow, Ph.D.</p>
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<p><strong><em>NIH Research Matters </em></strong>is a weekly update of NIH research highlights reviewed by NIH’s experts. It's published by the <a href="/institutes-nih/nih-office-director/office-communications-public-liaison">Office of Communications and Public Liaison</a> in the <a href="/institutes-nih/nih-office-director">NIH Office of the Director</a>.</p>
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<p>ISSN 2375-9593</p>
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