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Vol. 292, Issue 2, 654-663, February 2000

Facilitation of Constitutive alpha 2A-Adrenoceptor Activity by Both Single Amino Acid Mutation (Thr373Lys) and Galpha o Protein Coexpression: Evidence for Inverse Agonism

Petrus J. Pauwels, Stéphanie Tardif, Thierry Wurch and Francis C. Colpaert

Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, CASTRES Cédex, France.

The recombinant human alpha 2A-adrenoceptor (alpha 2A-AR, RC 2.1.ADR.A2A) can be transformed into a constitutively activated form in CHO-K1 cells by coexpression with a rat Galpha o protein. Constitutive activity could be enhanced more by both mutation of Thr373 of the alpha 2A-AR to a Lys and Cys351 of the Galpha o protein by an Ile. The basal [35S]GTPgamma S binding response displayed a constitutive alpha 2A-AR activity that amounted to 21% of the maximal receptor activation as obtained with 10 µM (-)-adrenaline. UK 14304, BHT 920, d-medetomidine, oxymetazoline, and clonidine acted as efficacious agonists. The enhancement of basal activity was entirely blocked (-50 ± 3%) by ligands that thus appeared to act as inverse agonists (i.e., RX 811059 and its (+)-enantiomer, (+)-RX 821002, RS 15385, and yohimbine); the potencies of the ligands corresponded with their binding affinities for the alpha 2A-AR. Fluparoxan and WB 4101 displayed partial inverse agonism. Atipamezole and dexefaroxan at 10 µM were virtually free of intrinsic activity and thus acted as neutral antagonists; idazoxan displayed potent partial agonist properties as observed with BRL 44408 and SKF 86466. The inverse agonist activity induced by (+)-RX 811059 could be reversed by atipamezole with a pKB value (8.73 ± 0.07) that was similar to that required for blockade of the UK 14304-mediated response. Constitutive alpha 2A-AR activation was mainly observed with the Galpha o Cys351Ile protein compared with the pertussis toxin-resistant mutants of the Galpha i protein subtypes. The observed spectrum of intrinsic activities for the various ligands suggests that pure, neutral antagonists are rather uncommon in this specified alpha 2A-AR system.

0022-3565/00/2922-0654$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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