Understanding why partial agonists of serotonin receptors do not produce maximal responses

CORRADI J.; BOUZAT, C.

Huerta Grande, Córdoba

Congreso; XXVII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencia; 2012

Partial agonists activate receptors with partial efficacy relative to full agonists. Our goal is to understand the reasons for which two classical partial agonists of 5HT3A receptors, 2-Me-5HT and tryptamine, produce submaximal responses. To this end, we recorded single channels of the high conductance form of the 5-HT3A receptor activated by 5-HT and partial agonists. For all agonists, activation appears as openings in quick succession grouped in clusters with high open probability (Popen>0.9). All recordings show the presence of three different open states. The longest duration state is 6.5- and 3.5-fold briefer for 2-Me-5HT and tryptamine, respectively, than for 5-HT. The duration of this open state decreases with agonist concentration due to open channel blockade. For 2-Me-5HT, the forward blocking rate is 10-fold higher than for tryptamine or 5-HT, and blockade leads to a reduction of Popen from 0.95 to 0.30 (from 1 to 50 ìM). Interpreting the data on the basis of kinetic schemes shows that 2-Me-5HT does not produce maximal response mainly because it acts as a potent channel blocker. In contrast, tryptamine is a genuine partial agonist and its low efficacy is mainly due to a slow transition from the fully-liganded closed state to a pre-open state. After reaching this latter state, activation proceeds similarly as in the presence of 5-HT.