New Insights on Serotonin Function and Subtypes Revealed

Researchers in China have revealed new insights into the structure and function of serotonin (5-HT), one of the main neurotransmitters in the human central nervous system and peripheral nervous system. With key regulatory roles in appetite, memory, cognition, and mood through serotonin receptors (5-HTR), the study could aid in the development of new drugs for multiple diseases.

The serotonin receptor family is one of the most complex subfamilies in 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 with different kinds of G proteins. Among them, the 5-HT4, 5-HT6, and 5-HT7 receptors are mainly coupled to downstream Gs proteins, and the 5-HT1 and 5-HT5 receptors are mainly coupled to downstream Gi proteins.

Notably, the study is first time researchers have reported the structures of the 5-HT4, 5-HT6, and 5-HT7 receptors, and resolved the structures of all 12 5-HT receptor subtypes. The team—led by H. Eric Xu from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences, in collaboration with researchers from Zhejiang University and the University of Copenhagen—systematically revealed the structural basis for the recognition of serotonin receptor subtypes by 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.

Through structural comparison of three Gs-coupled serotonin receptors to the Gi/o-coupled serotonin receptors, and to 19 additional Gs- and Gi/o-coupled class A receptor structures, the team uncovered a class-wide G protein selectivity mechanism that uses TM5 and TM6 switches. “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,” says Xu.

Furthermore, these structural insights into ligand recognition provide the foundation for rational structure-based drug design targeting the 5-HT4, 5-HT6, and 5-HT7 receptors. These insights also help clarify how to achieve ligand selectivity within the complex serotonergic system.

The study not only revealed the molecular mechanism of the selective coupling of G-proteins by class A GPCRs but also filled in the last gap in the structural analysis of 5-HT family receptors, according to the researchers. Since depression, schizophrenia, and migraine, etc. may be linked to serotonin, the research may also contribute to treatments for these diseases.

The findings were published recently in the journal Molecular Cell.