Expanding our knowledge about the structure and function of the serotonin type 3 receptor

Abstract

Serotonin (5-hydroxytryptamine: 5-HT) is a monoamine with diverse and important functions in nearly every living organism in the Earth. 5-HT3 receptors are the only members of the 5-HT receptors subfamily (5-HT1-7) that belong to the Cys-loop receptor family. They are ligand-gated ion channels that mediate fast synaptic responses in the central and peripheral nervous system and are implicated in many physiological and pathological processes, such as cognition, pain, vomiting reflex, depression, anxiety, among others. Five subunits have been identified in humans (A-E), where the A is the only capable of forming homomeric receptors (5- HT3A), and the B-E are accessory subunits that only form receptors by combining with A. Since its discovery, the 5-HT3A receptor has been widely studied through electrophysiological methods limited to the acquisition of macroscopic currents due to its very low conductance. By incorporation of a triple mutation in the intracellular loop we obtained a high-conductance receptor (5-HT3AHC). Using this model receptor, we were able to record single-channel events which, in combination with macroscopic currents, kinetics analysis and in silico studies, allowed us to reveal the mechanisms for receptor activation by full and partial agonists, and to identify sites and mechanisms of modulation. Our results also showed that the AHC subunit is a valuable tool for the elucidation of the stoichiometry of heteromeric receptors. All this information provides new clues for understanding about 5-HT3 receptors implication in human health and for the designing of more selective drugs.