Allosteric activation of the human 5-HT3A receptor

FABIANI, C.; RODRIGUEZ ARAUJO, N.; BOUZAT, C.; CORRADI, J.

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

The serotonin type 3 receptors (5-HT3) are cation-selective channels that belong to the Cys-loop receptor family. They are involved in fast excitatory transmission in central and peripheral nervous systems and are implicated in gastrointestinal and neurological functions. Five different subunits (A-E) have been identified in humans, and the A subunit is the only one capable of forming functional homopentameric receptors (5-HT3A). These receptors are activated by agonist binding to the orthosteric sites located at the interfaces between two adjacent subunits at the extracellular region. Ago-positive allosteric modulators (Ago-PAMs) are ligands that mediate a receptor response in the absence of an orthosteric agonist and also potentiates its response. We here used the high-conductance form of the receptor (5-HT3AHC), which allows detection of single-channel openings from patch-clamp recordings, to determine the molecular basis underlying its activation and modulation by two allosteric ligands, thymol and carvacrol. From cell-attached recordings, we observed that both ligands activate the receptor in a similar way, eliciting openings in quick succession that are grouped in episodes of high open probability (>0.9). The mean duration of the activation episodes in the presence of an allosteric agonist together with an orthosteric ligand (full or partial) were different to those obtained in the presence of each type of agonist .