INIBIBB   05455
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE BAHIA BLANCA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Mechanism of activation of the 5-HT3A receptor by partial agonists.
Autor/es:
JEREMÍAS CORRADI; CECILIA BOUZAT
Lugar:
Sierra de la Ventana
Reunión:
Congreso; XLIII Reunión Anual SAB 2014; 2014
Institución organizadora:
Sociedad argentina de biofísica
Resumen:
Partial agonists have emerged as attractive therapeutic
molecules. 2-Me-5HT and tryptamine have been defined as partial agonists of
5-HT3 receptors on the basis of macroscopic measurements. Because
several mechanisms may limit maximal responses we took advantage of the
high-conductance form of the mouse 5-HT3A receptor to understand
their molecular actions. Individual 5-HT-bound receptors activate in long
episodes of high open probability, consisting of groups of openings in quick
succession. The activation pattern is similar for 2-Me-5HT only at very low
concentrations since profound channel blockade takes place within the
activating concentration range. In contrast, activation episodes are
significantly briefer in the presence of tryptamine. Generation of a full
activation scheme reveals that the fully-occupied receptor overcomes
transitions to closed pre-open states (primed states) before opening. Reduced
priming explains the partial agonism of tryptamine. In contrast, 2-Me-5HT is
not a genuine partial agonist since priming is not dramatically affected and
its low apparent efficacy is mainly due to channel blockade. The analysis also
shows that the first priming step is the rate-limiting step and partial
agonists require an increased number of priming steps for activation. Molecular
docking suggests that interactions are similar for 5-HT and 2-Me-5HT but
slightly different for tryptamine. Our study contributes to understanding 5-HT3A
receptor activation, extends the novel concept of partial agonism within the
Cys-loop family, reveals novel aspects of partial agonism, and unmasks
molecular actions of classically-defined partial agonists. Unraveling
mechanisms underlying partial responses has implications in the design of
therapeutic compounds