A single channel mutation alters agonist efficacy at 5-HT3A and 5-HT3AB receptors.
Br J Pharmacol
; 170(2): 391-402, 2013 Sep.
Article
en En
| MEDLINE
| ID: mdl-23822584
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. EXPERIMENTALAPPROACH:
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. KEYRESULTS:
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.Palabras clave
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Banco de datos:
MEDLINE
Asunto principal:
Serotonina
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Receptores de Serotonina 5-HT3
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Agonistas del Receptor de Serotonina 5-HT3
Límite:
Animals
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Female
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Humans
Idioma:
En
Año:
2013
Tipo del documento:
Article