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-HT3A receptors with the aim of fin...

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Published in:	Biochimica et biophysica acta Vol. 1828; no. 11; pp. 2564 - 2573
Main Authors:	Meiboom, M.F., Barann, M., Witten, S., Groeneveld, K., Urban, B.W.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-11-2013
Subjects:	5-Hydroxytryptamine derivative Agonist Amines - pharmacology Anesthetic HEK293 Cells Human 5-HT3A receptor Humans Patch-clamp Patch-Clamp Techniques Phenol - pharmacology Pyrroles - pharmacology Receptors, Serotonin, 5-HT3 - drug effects Receptors, Serotonin, 5-HT3 - metabolism Serotonin Receptor Agonists - administration & dosage Serotonin Receptor Agonists - pharmacology Tyramine Human 5-HT3A receptor Tyramine Agonist 5-Hydroxytryptamine derivative Anesthetic Patch-clamp Human 5-HT(3A) receptor
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Summary:	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-HT3A 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-HT3A 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-HT3A 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. [Display omitted] •Each functional group of 5-HT interacts with a subsite in the h5-HT3A receptor.•Molecules representing a single functional group of 5-HT are not agonists.•Agonists of the h5-HT3A receptor require interactions with at least two subsites.•Agonist interactions have to be of adequate strength and steric configuration.•Anesthetics appear not to fulfill these requirements for agonist action.
ISSN:	0005-2736 0006-3002 1879-2642
DOI:	10.1016/j.bbamem.2013.06.013