ALLOSTERIC ACTIVATION OF THE HUMAN 5-HT3 RECEPTOR

CAMILA FABIANI; NOELIA RODRÍGUEZ ARAUJO; CECILIA BOUZAT; JEREMÍAS CORRADI

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

The serotonin type 3 receptors (5-HT3) are cation-selective channelsthat belong to the Cys-loop receptor family. They are involvedin fast excitatory transmission in central and peripheral nervous systemsand 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 homopentamericreceptors (5-HT3A). These receptors are activatedby agonist binding to the orthosteric sites located at the interfacesbetween two adjacent subunits at the extracellular region. Ago-positiveallosteric modulators (Ago-PAMs) are ligands that bind to anallosteric binding site and mediate a receptor response in the absenceof an orthosteric agonist and also potentiate its response. Wehere 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 activationand modulation by two ago-PAMs, thymol and carvacrol. Fromcell-attached recordings, we observed that both ligands activate thereceptor in a similar way, eliciting openings in quick succession thatare grouped in episodes (bursts) of high open probability (>0.9). Thecombined application of orthosteric agonists (full or partial) with theallosteric ligands elicits single channel events whose mean openand burst durations are intermediate between those obtained whenorthosteric or allosteric agonists are applied individually.Our results reveal the mechanistic basis underlying activation andmodulation of the 5-HT3A receptor by two ago-positive allostericmodulators, thus providing new information that is essential for thedesign of more efficacious and specific therapeutic compounds.