Scientists are making a breakthrough in understanding serotonin receptors

Summary: Researchers have resolved the structures of all 12 serotonin receptor subtypes.

Source: Chinese Academy of Sciences

Serotonin (5-HT) is one of the major neurotransmitters in the human central and peripheral nervous system. Helps regulate appetite, memory, cognition and mood through serotonin receptors (5-HTR).

A group of international scientists recently made a breakthrough in understanding the structure and function of serotonin receptors. This is the first time researchers have reported on the structures of 5-HT45-HT6and 5-HT7 receptors and resolves the structures of all 12 5-HT receptor subtypes.

The study is published online at Molecular cell on June 16.

Researchers led by H. Eric Xu of the Shanghai Institute of Matter (SIMM) of the Chinese Academy of Sciences, in collaboration with researchers from Zhejiang University and the University of Copenhagen, systematically uncovered the structural basis for recognizing serotonin receptor subtypes from low molecular weight ligands 5 -HT and 5-CT.

They also elucidate the molecular mechanism for the selective binding of Gs and Gand serotonin receptor proteins.

The serotonin receptor family is one of the most complex subfamilies in the G-protein-coupled receptor (GPCR) superfamily and contains 12 subtypes. Different subtypes of receptors play different physiological roles in the human body and are combined with different types of G proteins.

Among them 5-HT45-HT6and 5-HT7 receptors are mainly bound to Gs proteins and 5-HT1 and 5-HT5 receptors are mainly bound to Gand proteins.

By structural comparison of these three Gs-bound serotonin receptors to GI / o-bound serotonin receptors and up to 19 additional Gs– and GI / o-connected class A receptor structures, the team discovered a G-protein selectivity mechanism throughout the class that uses TM5 and TM6 switches.

“These findings improve the fundamental understanding of how serotonin receptors, the largest subfamily of Class A GPCRs activated by the same endogenous ligand, generate their wide variety of cellular responses,” said Sue, the study’s author.

This is the first time researchers have reported the structures of 5-HT4, 5-HT6 and 5-HT7 receptors and have resolved the structures of all 12 subtypes of 5-HT receptors. The image is in the public domain

In addition, these structural insights into ligand recognition provide the basis for a rational structural design of 5-HT-targeted drugs.45-HT6and 5-HT7 receptors. These insights also help to clarify how to achieve ligand selectivity within a complex serotonergic system.

The achievement not only revealed the molecular mechanism of selective binding of G-proteins of class A GPCR, but also filled the last gap in the structural analysis of receptors from the 5-HT family, according to researchers.

These systematic studies of serotonin receptors have greatly enriched our understanding of the structure and function of the serotonin system. Because depression, schizophrenia, migraine, etc. can be associated with serotonin, this study may also contribute to the treatment of these diseases.

For this news on serotonin testing

author: Na Chen
Source: Chinese Academy of Sciences
contact: Chen – Chinese Academy of Sciences
Image: The image is in the public domain

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Original research: Closed access.
“GPCRs control Gi and Gs selectivity through TM5-TM6 switches as revealed by serotonin receptor structures” by H. Eric Xu et al. Molecular cell


GPCRs control Gi and Gs selectivity through TM5-TM6 switches as revealed by serotonin receptor structures

Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) by selectively binding GsMr.I, or Dq proteins. The structural basis for the selectivity of the G protein subtype of these GPCRs remains elusive.

Here we report on the structures of serotonin 5-HT receptors45-HT6and 5-HT7 with Gsand 5-HT4 with Gi1. The structures reveal that the TM5 and TM6 transmembrane helices alternate lengths as a macro switch to determine the selectivity of the G receptors and Gandrespectively.

We find that the macro switch along the TM5-TM6 is shared by class A GPCR-G protein structures. In addition, we find specific residues in TM5 and TM6 that function as microswitches to form specific interactions with Gs or Dand.

Together, these results represent a common mechanism of Gs against Gand selectivity or promiscuity of binding to class A GPCR proteins and broaden the basis of ligand recognition at serotonin receptors.

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