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

Abstract

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 μM). 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