Scientists have made progress in understanding serotonin receptors

Summary: The researchers solved the structures of all 12 subtypes of serotonin receptors.

Source: Chinese Academy of Sciences

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

An international team of scientists has recently made a breakthrough in understanding the structure and function of serotonin receptors. This is the first time researchers have reported on the structure of 5-HT45-HT6and 5-HT7 receptors, and resolved the structures of all subtypes of 12 5-HT receptors.

The study was published online Molecular Cell June 16th.

Researchers led by H. Eric Xu of the Shanghai Institute of Materia Medica (SIMM) at the Chinese Academy of Sciences, in collaboration with researchers from Zhejiang University and the University of Copenhagen, systematically revealed the structural basis for knowing the subtypes of serotonin receptors. low-molecule 5-HT and 5-CT ligands.

They also elucidated the molecular mechanism for selective coupling of Gs and Gi proteins through serotonin receptors.

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

These include 5-HT45-HT6and 5-HT7 the receptors are mostly coupled to the lower Gs proteins, and 5-HT1 and 5-HT5 the receptors are mostly coupled to the lower Gi proteins.

Through a structural comparison of these three Gss– Couples serotonin receptors Gi / o-coupled serotonin receptors, and 19 G supplements-and Gi / oCoupled Class A receptor structures, the group found a mechanism of G protein selectivity for the entire class using TM5 and TM6 switches.

“These findings show how serotonin receptors, the largest class A GPCR subfamily activated by the endogenous ligand itself, produce a wide variety of cellular responses,” said study author Xu.

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

Moreover, these structural approaches to the recognition of ligands provide the basis for the rational design of drugs based on the 5-HT structure.45-HT6and 5-HT7 recipients. These approaches also help shed light on how to achieve ligand selectivity in the complex serotonergic system.

This achievement revealed the molecular mechanism of selective G-protein coupling of class A GPCRs, but also filled the final gap in the structural analysis of 5-HT family receptors, according to the researchers.

These systematic studies of serotonin receptors have greatly enriched the understanding of the structure and function of the serotonin system. Because depression, schizophrenia, and migraines, etc. may be linked to serotonin, this research may also help in the treatment of these diseases.

About this serotonin research news

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

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Original research: Closed access.
“GPCRs drive Gi and Gs selectivity through TM5-TM6 switches according to serotonin receptor structures” H. Eric Xu et al. Molecular Cell


Abstract

GPCRs drive Gi and Gs selectivity through TM5-TM6 switches, as evidenced by serotonin receptor structures.

Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates different 12 G protein-coupled receptors (GPCRs) through selective G-coupling.sGi, or Gq proteins. The structural basis for the selectivity of the G protein subtype of these GPCRs remains elusive.

Here, we report the 5-HT structure of serotonin receptors45-HT6and 5-HT7 With Gsand 5-HT4 With Gi1. The structures reveal that the TM5 and TM6 transmission helices alternate in length as macro-switches to determine G receptor selectivity.s and Girespectively.

We find that the TM5-TM6 length macro-switch is shared by the structures of the class A GPCR-G protein. In addition, we find specific wastes that function as micro-switches within TM5 and TM6 to generate specific interactions with G.s or Gi.

Together with these results, they present a common mechanism of Gs G versusi selectivity or promiscuity for protein coupling through class A GPCRs and broadening the basis for ligand recognition in serotonin receptors.

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