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Developmental biology - The Cell Membrane

A First Time Look At How Serotonin Opens Receptors

A first description of how serotonin activates full-length receptor down to individual atoms...

Serotonin receptors are common drug targets for dulling pain, gastrointestinal dysfunction, and mood disorders. But little is known about this three-dimensional structure. Details about the serotonin receptor structure could give important clues to designing better drugs with less side effects. And now, for the first time, a team from Case Western Reserve University School of Medicine uses high-powered microscopes, so that researchers can view serotonin ataching to its receptor on a cell surface. The work is published in Nature and reveals details about receptors that could improve drug design and treat a multitude of diseases.

Serotonin receptors dot the surface of cell membranes throughout the body, including the brain, stomach, and the nervous system. Drugs that inhibit serotonin receptors help control post-operative nausea, support cancer therapies, and treat gastrointestinal conditions like irritable bowel syndrome. They also are used as anti-depressants, while promoting attention and memory. But broad application comes with side effects - partly due to less than optimal drug-receptor interactions.
"Successful design of safer therapeutics has been slowed because there is a limited understanding of the structure of the serotonin receptor itself, and what happens after serotonin binds to it. Our work is the first to describe how serotonin activates the full-length serotonin receptor down to the level of detail nearly at the individual atom."

Sudha Chakrapani PhD, Associate Professor of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Using prize-winning microscopy, Chakrapani's team studied serotonin as it interacted with its receptor revealing that serotonin attaches to the receptor and twists open the channel.

Open channels allow molecules to travel from outside the cell to inside. Researchers watched as sodium molecules passed through newly opened channels, highlighting distinct shapes conforming to the serotonin receptor. Receptors make a cell permeable to certain molecules - a key insight for drug developers. They also revealed which portions of the receptor are critical for proper functioning of the channel.

An entire serotonin-receptor occupies a space about a few billionths of a meter across. Microscopes only recently are able to capture such tiny molecules as the cutting-edge technology 'cryo-electron microscopy' recently earning a 2017 Nobel Prize in chemistry. High-powered microscopes take snapshots of proteins in action, compiling them into three-dimensional models. In the past year this technology has helped research at Case Western Reserve to view proteins in kidney stones and other ailments. Chakrapani used "cryo-EM" last year to look only at the serotonin receptor, laying the foundation for this present study. The hope is that these findings lead to drugs targeted to specific regions and functions of specific serotonin receptors.
"It's likely new and different drugs can work as effective serotonin inhibitors, especially if they're designed to work differently than current drugs. We're actively pursuing approaches to help design safer therapeutics to modulate the serotonin receptor and treat a range of conditions."

Sandip Basak PhD, postdoctoral fellow in Chakrapani's lab and first author.

The 5-HT3A serotonin receptor1, a cationic pentameric ligand-gated ion channel (pLGIC), is the clinical target for management of nausea and vomiting associated with radiation and chemotherapies2. Upon binding, serotonin induces a global conformational change that encompasses the ligand-binding extracellular domain (ECD), the transmembrane domain (TMD) and the intracellular domain (ICD), the molecular details of which are unclear. Here we present two serotonin-bound structures of the full-length 5-HT3A receptor in distinct conformations at 3.32 ┼ and 3.89 ┼ resolution that reveal the mechanism underlying channel activation. In comparison to the apo 5-HT3A receptor, serotonin-bound states underwent a large twisting motion in the ECD and TMD, leading to the opening of a 165 ┼ permeation pathway. Notably, this motion results in the creation of lateral portals for ion permeation at the interface of the TMD and ICD. Combined with molecular dynamics simulations, these structures provide novel insights into conformational coupling across domains and functional modulation.

Sandip Basak, Yvonne Gicheru, Shanlin Rao, Mark S. P. Sansom & Sudha Chakrapani.

This research was supported in part by the National Cancer Instituteĺs National Cryo-EM Facility at the Frederick National Laboratory for Cancer Research, and we thank them for the imaging time. We thank the Cleveland Center for Membrane and Structural Biology for the access to cryo-EM instrumentation, D. Major for assistance with hybridoma and cell culture at Department of Ophthalmology and Visual Sciences (NIH Core Grant P30EY11373), W. Boron for Xenopus oocytes and access to the oocyte rig, and G. Klesse and S. Tucker for the Channel Annotation Package methodology. This work was supported by an NIH grant (1R01GM108921), a cryo-EM supplement (3R01GM108921-03S1) to S.C. and an AHA postdoctoral Fellowship to S.B. (17POST33671152).

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Nov 6, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

After serotonin attaches to the receptor it twists open the channel.
Image Credit: Case Western Reserve University School of Medicine

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