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<h2 class="element-invisible">You are here</h2><div class="breadcrumb"><a href="/">Home</a> » <a href="/news-events">News & Events</a> » <a href="/news-events/nih-research-matters">NIH Research Matters</a></div> <div class="l-region l-region--section-header">
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<p class="publishdate"><span property="dc:date" datatype="xsd:dateTime" content="2016-04-19T00:00:00-04:00" class="date-display-single">April 19, 2016</span></p><div class='syndicate'><h1>Serotonin transporter structure revealed</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 3-D structure of the serotonin transporter and visualized how 2 common antidepressants interact with the protein.</li>
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<li>The findings provide insights for designing new ways to target the transporter for more effective medications.</li>
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<picture title="Human serotonin transporter structure">
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<!--[if IE 9]><video style="display: none;"><![endif]-->
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-large/public/news-events/research-matters/2016/20160414-serotonin.jpg?itok=79j8QzeD&timestamp=1461070874 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/2016/20160414-serotonin.jpg?itok=yYVSvbk5&timestamp=1461070874 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/2016/20160414-serotonin.jpg?itok=wXC-9feJ&timestamp=1461070874 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/2016/20160414-serotonin.jpg?itok=yTZr_E09&timestamp=1461070874 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/2016/20160414-serotonin.jpg?itok=3-k-UU2T&timestamp=1461070874 1x" media="screen and (min-width: 0)" />
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<!--[if IE 9]></video><![endif]-->
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<img src="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2016/20160414-serotonin.jpg?itok=yYVSvbk5&timestamp=1461070874" alt="Human serotonin transporter structure" title="Human serotonin transporter structure" />
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</picture><span class="caption">Slice through the human serotonin transporter structure illustrating the SSRI binding sites. Citalopram is shown at the central site in purple and at the allosteric site in yellow. </span><span class="credit">Jonathan A. Coleman, Evan M. Green, and Eric Gouaux, Oregon Health and Science University</span></div>
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</div><p>Antidepressants are used to treat depression as well as other health conditions, such as anxiety, pain, and insomnia. Some of the most common antidepressants are called selective serotonin reuptake inhibitors (SSRIs). These work by increasing the amount of available serotonin, a chemical messenger that helps brain cells, or neurons, communicate. Serotonin levels affect sleep, mood, cognition, pain, hunger, and even aggressive behaviors.</p>
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||
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<p>After being released into the gaps between neurons, serotonin is pumped back for reuse into the cell that released it via the serotonin transporter protein. SSRIs slow this recycling process by blocking the pump, leaving the serotonin accessible to other neurons.</p>
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||
<p>A research team led by Dr. Eric Gouaux of Oregon Health and Science University set out to solve the structure of the human serotonin transporter and determine how SSRIs interact with it. The research was funded in part by NIH’s National Institute of Mental Health (NIMH). Results were published online in <em>Nature</em> on April 6, 2016.</p>
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||
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||
<p>The serotonin transporter can be difficult to prepare for X-ray crystallography, a technique that creates an image of a protein’s 3-D structure. The protein is normally unstable during the purification and crystallization processes. The researchers genetically altered the transporter to withstand the temperatures used for isolation. They also added small antibody fragments to the protein solution to encourage crystallization. Using these modifications, they were able to create small crystals suitable for X-ray crystallography.</p>
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||
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||
<p>The technique yielded a detailed molecular map of the human serotonin transporter’s structure. The scientists were able to identify where different molecules interact with the transporter, including the sodium and chloride ions that are necessary for pumping serotonin.</p>
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||
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||
<p>The group next determined where 2 SSRIs, citalopram (CeleXA) and paroxetine (Paxil), take hold of the transporter. They found that both bind to the pump’s primary central binding site, preventing serotonin from binding and being pumped into the neuron. The SSRIs also fit in a second site on the protein, called an “allosteric” site, which affects how quickly molecules can get out of the central pocket. Thus, compounds that bind to this allosteric site can affect transport activity as well.</p>
|
||
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<p>The researchers could also see where genetic variations associated with various psychiatric disorders are located in the transporter. Knowing the structure of the transporter can help researchers gain insights into the molecular causes of these disorders and of antidepressant treatment resistance.</p>
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<p>“The heavy toll that devastating illnesses like anxiety and depression have on families and communities is, in many ways, incalculable,” says Gouaux. “Revealing the precise structure of the serotonin transporter holds promise for the development of life-changing drug treatments for these diseases.”</p>
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<p>—by Tianna Hicklin, Ph.D.</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/predicting-treatment-response-rapid-antidepressant" target="_top">Predicting Treatment Response to a Rapid Antidepressant</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/placebo-effect-depression-treatment" target="_top">Placebo Effect in Depression Treatment</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/brain-scan-may-predict-best-depression-treatment" target="_top">Brain Scan May Predict Best Depression Treatment</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/genetic-switch-involved-depression" target="_top">Genetic Switch Involved in Depression</a></li><li><a href="https://newsinhealth.nih.gov/issue/mar2016/feature1" target="_top">Understanding Anxiety Disorders</a></li><li><a href="http://www.nimh.nih.gov/health/topics/mental-health-medications/index.shtml#part_149856" target="_top">Antidepressants</a></li><li><a href="http://www.nimh.nih.gov/health/topics/depression/index.shtml" target="_top">Depression</a></li><li><a href="http://www.nimh.nih.gov/health/topics/mental-health-medications/index.shtml" target="_top">Mental Health Medications</a></li></ul><p class="footnote"><strong class="label-inline">References: </strong><a href="https://www.ncbi.nlm.nih.gov/pubmed/27049939">X-ray structures and mechanism of the human serotonin transporter.</a> Coleman JA, Green EM, Gouaux E. <em>Nature</em>. 2016 Apr 6. doi: 10.1038/nature17629. [Epub ahead of print]. PMID: 27049939.</p><p class="footnote"><strong class="label-inline">Funding: </strong>NIH’s National Institute of Mental Health (NIMH) and Howard Hughes Medical Institute.</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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