Scientists advance understanding of serotonin receptors

Molecular Cell (2022). DOI: 10.1016/j.molcel.2022.05.031″ width=”800″ height=”530″/>

Graphic abstract. Credit: Molecular Cell (2022). DOI: 10.1016 / j.molcel.2022.05.031

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

A group of international scientists has recently made a breakthrough in understanding the structure and function of serotonin receptors. This is the first time that researchers report the structures of 5-HT45-HT6and 5-HT7 receptors, and resolved the structures of all 12 5-HT receptor subtypes.

The study was published online at Molecular Cell on June 16th.

Researchers led by H. Eric Xu of the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences, in collaboration with researchers from Zhejiang University and Copenhagen University, have systematically revealed the structural basis for the recognition of receptor subtypes of serotonin via the small molecule ligands 5-HT and 5-CT. They also elucidated the molecular mechanism for the selective coupling of Gs and GI proteins by serotonin receptors.

The serotonin receptor family is one of the most complex subfamilies of the G protein-coupled receptor (GPCR) superfamily and contains 12 subtypes. Different receptor subtypes play different physiological roles in the human body and are coupled to different types of G proteins. Among them, 5-HT45-HT6and 5-HT7 receivers are mostly G-coupled downstreams proteins and 5-HT1 and 5-HT5 receivers are mostly G-coupled downstreamI proteins.

Through the structural comparison of these three Gs-couples serotonin receptors to Gme/them-coupled serotonin receptors and additional 19 Gs– and Gme/them-coupled to class A receptor structures, the team discovered a mechanism of class-wide G protein selectivity that uses switches TM5 and TM6.

“These findings advance the fundamental understanding of how serotonin receptors, the largest subfamily of class A GPCRs activated by the same endogenous ligand, create their wide diversity of cellular responses,” said Xu, corresponding author of the study.

Furthermore, these structural insights into ligand recognition provide the basis for rational design of structure-based drugs targeting 5-HT.45-HT6and 5-HT7 receivers. These insights also help to clarify how to achieve ligand selectivity within the complex serotonergic system.

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

These systematic studies of serotonin receptors have greatly enriched our understanding of the structure and function of the serotonin system. As depression, schizophrenia and migraines may be linked to serotonin, this research may also contribute to treatments for these conditions.

Researchers reveal how lipids and water molecules regulate 5-HT receptors

More information:
Sijie Huang et al, GPCRs direct the selectivity of Gi and Gs through TM5-TM6 switches, as revealed by serotonin receptor structures, Molecular Cell (2022). DOI: 10.1016 / j.molcel.2022.05.031

Provided by the Chinese Academy of Sciences

Quote: Scientists advance understanding of serotonin receptors (2022, June 17) retrieved June 17, 2022 from

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