Electrophysiological characterization of human heteromeric 5-HT3 receptors.

JEREMÍAS CORRADI; CECILIA BOUZAT

Salto

Congreso; Latin American Crosstalk in Biophysics and Physiology. SBF.uy-SAB; 2015

5-HT3 receptors are members of theCys-loop receptor family. They mediate fast excitatory transmission both incentral and peripheral nervous system. Genes for five different subunits (5-HT3A-E) have been identified in humans, and most of the subunits have multiple isoforms.The 5-HT3A subunit is the only one that forms functional homopentamericreceptors or it can combine with the 5-HT3B subunit to form heteropentamericreceptors. Apart from 5-HT3AB receptors, the combination of the 5-HT3Awith other subunits has not been extensively investigated yet. We here performsingle-channel and macroscopic current recordings to determine if 5-HT3A canassemble with B, C, D or E subunits (B-E subunits). The B-E subunits arenon-functional when expressed alone since no 5-HT activated currents aredetected. However, after co-expression of 5-HT3A subunit with each of the B-Esubunits, opening events with different single-channel conductance and kineticproperties, with respect to that of 5-HT3A receptors, are detected.These results demonstrate that each of B-E subunits can form functionalreceptors with 5-HT3A. We also evaluated the role of two isoforms of the Bsubunit, 5-HT3Br1 and 5-HT3Br2, which are highly expressed in human brain. Ourdata show that the Br1 variant when co-expressed with the A subunit alters the macroscopicand single-channel responses of the 5-HT3A receptor in a similar wayas the 5-HT3B subunit. Conversely, the Br2 subunit does not appear to formfunctional channels with 5-HT3A, and the role of this subunit is yet to bedetermined. Therefore, our results demonstrate the possible incorporation ofdifferent 5-HT3 subunits to the receptor, thus leading to a wide variety ofreceptors showing different functional properties, such as agonist sensitivity,kinetics and single-channel conductance. The functional characterization ofdifferent heteromeric 5-HT3 receptors, which are expressed indifferent tissues, contributes to the development of selective therapiestargeting this receptor family.