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

JEREMÍAS CORRADI

La Plata

Congreso; XLVII Reunión Anual SAB; 2018

Sociedad Argentina de Biofísica

Serotonin (5-hydroxytryptamine: 5-HT) is a monoamine with diverse andimportant functions in nearly every living organism in the Earth. 5-HT3receptors 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 channelsthat mediate fast synaptic responses in the central and peripheral nervoussystem and are implicated in many physiological and pathological processes,such as cognition, pain, vomiting reflex, depression, anxiety, among others. Fivesubunits have been identified in humans (A-E), where the A is the only capable offorming homomeric receptors (5-HT3A), and the B-E are accessorysubunits that only form receptors by combining with A. Since its discovery, the5-HT3A receptor has been widely studied through electrophysiologicalmethods limited to the acquisition of macroscopic currents due to its very lowconductance. By incorporation of a triple mutation in the intracellular loop weobtained a high-conductance receptor (5-HT3AHC). Usingthis model receptor, we were able to record single-channel events which, incombination with macroscopic currents, kinetics analysis and in silico studies, allowed us to reveal themechanisms for receptor activation by full and partial agonists, and toidentify sites and mechanisms of modulation. Our results also showed that the AHCsubunit is a valuable tool for the elucidation of the stoichiometry of heteromericreceptors. All this information provides new clues for understanding about 5-HT3receptors implication in human health and for the designing of more selectivedrugs.