Mutations of L293 in transmembrane two of the mouse 5-hydroxytryptamine3A receptor alter gating and alcohol modulatory actions

British Journal of Pharmacology
Xiang-Qun HuTina K Machu

Abstract

1 The goal of this study was to determine whether mutations of L293 at the 15' position of TM2 in the 5-HT(3A) receptor alter macroscopic current kinetics, and if these changes could account for alterations in alcohol modulation. Receptor function was assessed in Xenopus oocytes under voltage-clamp and in HEK293 cells with whole-cell patch-clamp recording and rapid drug application. 2 Examination of responses of L293C and L293S receptors to agonist alone revealed enhanced activation, deactivation, and desensitization rates relative to the wild-type receptor. The L293G mutation produced marked slowing of deactivation and desensitization rates. Increased potency of 5-HT and increased efficacy of the partial agonist, DA, was also observed in these mutant receptors. 3 Ethanol and trichloroethanol (TCEt) enhancement of receptor function was reduced or eliminated in receptors containing L293 mutations to C, G, or S. The L293I mutant receptor retained ethanol and TCEt sensitivity. Ethanol and TCEt enhanced activation rate in the wild-type, but not the L293G and L293S receptors. No relationship was observed between any physicochemical property of the substituted amino acids and the change in alcohol potentiation of function. 4 The chan...Continue Reading

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Citations

Feb 2, 2012·Journal of Chemical Biology·Tapan Kumar NayakSujit K Sikdar
Mar 5, 2010·The Journal of Pharmacology and Experimental Therapeutics·Paula L Feinberg-Zadek, Paul A Davies
Mar 10, 2009·Pharmacological Reviews·Alex M Dopico, David M Lovinger
Jul 5, 2013·British Journal of Pharmacology·A J Thompson, S C R Lummis
Oct 24, 2014·The Journal of Pharmacology and Experimental Therapeutics·Carlos F BurgosLuis G Aguayo
Dec 21, 2007·The Journal of Pharmacology and Experimental Therapeutics·Xiang-Qun Hu, Robert W Peoples
Jan 18, 2011·The Journal of Pharmacy and Pharmacology·Zane DzirkaleVija Klusa
May 15, 2015·Alcoholism, Clinical and Experimental Research·Suzzane HoraniRebecca J Howard
Mar 22, 2007·Expert Opinion on Therapeutic Targets·Andrew J Thompson, Sarah C R Lummis
Apr 19, 2013·British Journal of Pharmacology·Amy S NewmanNicholas M Barnes

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