Which agonist properties are important for the activation of 5-HT3A receptors?

Purpose: Why do anesthetics not activate excitatory ligand-gated ion channels such as 5-HT₃ receptors in contrast to inhibitory ligand-gated ion channels? This study examines the actions of structural closely-related 5-HT derivatives and 5-HT constituent parts on 5-HT_3A receptors with the aim of finding simpler if not minimal agonists and thus determining requirements for successful agonist action. Experimental approach: Responses to 5-HT derivatives of human 5-HT_3A receptors stably expressed in HEK 293 cells have been examined with the patch-clamp technique in the outside-out configuration combined with a fast solution exchange system. Results: Phenol, pyrrole and alkyl amines, constituents of 5-HT, even at high concentrations, cannot activate 5-HT_3A receptors but they can inhibit them. To date, tyramines are the smallest known agonists. However, an aromatic ring is not required for activation as acetylcholine is also an agonist of similar strength. Conclusion: Simultaneous interactions of adequate strength at two separate subsites within the 5-HT binding domain appear to be essential for successful agonist function. Anesthetics either fail to achieve this or the activation they produce is so weak that it is masked by a comparatively very strong inhibition.