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Br J Pharmacol. 2013 Sep;170(2):391-402. doi: 10.1111/bph.12287.

A single channel mutation alters agonist efficacy at 5-HT3A and 5-HT3AB receptors.

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  • 1Department of Biochemistry, University of Cambridge, Cambridge, UK.

Abstract

BACKGROUND AND PURPOSE:

5-HT3 receptors are composed of 5-HT3A subunits (homomeric receptors), or combinations of 5-HT3A and other 5-HT3 receptor subunits (heteromeric receptors, the best studied of which are 5-HT3AB receptors). Here we explore the effects of partial agonists at 5-HT3A and 5-HT3AB receptors, and the importance of a channel-lining residue in determining the efficacy of activation.

EXPERIMENTAL APPROACH:

Wild type and mutant 5-HT3A and 5-HT3AB receptors were expressed in Xenopus oocytes and examined using two-electrode voltage-clamp, or expressed in HEK293 cells and examined using [(3)H]granisetron binding.

KEY RESULTS:

Dopamine, quipazine and VUF10166 were partial agonists at wild type 5-HT3A and 5-HT3AB receptors, with quipazine and VUF10166 causing a long-lived (>20 min) inhibition of subsequent agonist responses. At 5-HT3A receptors, mCPBG was a partial agonist, but was a superagonist at 5-HT3AB receptors, as it produced a response 2.6× greater than that of 5-HT. A T6'S substitution in the 5-HT3A subunit decreased EC50 and increased Rmax of dopamine and quipazine at both homomeric and heteromeric receptors. The greatest changes were seen with VUF10166 at 5-HT3AT6'SB receptors, where it became a full agonist (EC50 = 7 nM) with an EC50 58-fold less than 5-HT (EC50 = 0.4 μM) and no longer caused inhibition of subsequent agonist responses.

CONCLUSIONS AND IMPLICATIONS:

These results indicate that a mutation in the pore lining domain in both 5-HT3A and 5-HT3AB receptors alters the relative efficacy of a series of agonists, changing some (e.g. quipazine) from apparent antagonists to potent and efficacious agonists.

© 2013 The Authors. British Journal of Pharmacology published by John Wiley &. Sons Ltd on behalf of The British Pharmacological Society.

KEYWORDS:

Cys-loop; binding; gating; heteromeric; ligand-gated ion channel; serotonin

PMID:
23822584
[PubMed - indexed for MEDLINE]
PMCID:
PMC3834762
Free PMC Article
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