Mechanistic basis of partial agonism at 5-HT3A receptors

CORRADI J.; BOUZAT, C.

Philadelphia

Congreso; 57th Annual Meeting Biophysical Society; 2013

Biophysical Society

Partial agonists are unable to elicit full maximal responses. The characterization of a genuine partial agonist iscomplex because other mechanisms, such as channel block, may also limit maximum open probability. Takingadvantage of the high conductance form of the 5-HT3A receptor, we evaluated at the single-channel level itsactivation by 2-Me-5HT and tryptamine, which have been classically considered as partial agonists of 5-HT3receptors. For all ligands, activation appears as openings in quick succession grouped in clusters showing highopen probability (Popen>0.9), and open time distributions show three components. The slowest opencomponent is 6.5- and 3.5-fold briefer for 2-Me-5HT and tryptamine, respectively, than for 5-HT. Theduration of this component decreases as a function of agonist concentration due to open-channel block. For2-Me-5HT, the forward blocking rate is 10-fold faster than for tryptamine and 5-HT. Single-channel kineticanalysis shows that 2-Me-5HT is actually a full agonist, its maximum response being limited by channel block.In contrast, tryptamine is a genuine partial agonist and its low efficacy is mainly due to a slow transition fromthe fully-liganded closed state to a pre-open state. After reaching the latter state, activation proceeds similarlyas in the presence of 5-HT. Molecular docking shows that interactions at the binding site are similar for2-Me-5HT and 5-HT. In contrast, the potential to form the cation-Pi interaction with W183 seems to bereduced for tryptamine. The mechanism by which ligands produce non maximal responses has implications forthe design of partial agonists for therapeutic use.