The serotonin-gated 5-HT3 receptor: a tale of functions and structures of a prototypical pentameric ligand-gated ion channel
Abstract
Serotonin-gated 5-HT3 receptors (5-HT3Rs), which belong to the cys-loop superfamily of ligand-gated ion channels, mediate fast excitatory neurotransmission in the central and peripheral nervous system. They are targets for drugs to treat neurological diseases and psychiatric disorders, as well as chemotherapy-induced and postoperative nausea and emesis. The ever-increasing number of resolved 3D structures of the homopentameric form of 5-HT3AR, in combination with new computational approaches allow us to better understand the molecular processes of ligand binding, the subsequent conformational changes, and ion permeation, providing a solid foundation for understanding the biological functions of 5-HT3AR and its heteropentameric 5-HT3R homologs. In this review, we first outline the physiological roles and subunit assembly of heteromeric 5-HT3Rs, which predominate in vivo. We then summarize the latest structural insights into the 5-HT3AR, revealing details of its architecture, ligand-binding sites, and conformational transitions leading to channel activation. Finally, we discuss the evolving pharmacology of 5-HT3R modulators and provide our perspectives on future research directions aimed at resolving the heteropentameric structures of 5-HT3R in their native membrane and developing modern drugs targeting these receptors.