Evidence for protean agonism of RX 831003 at α2A-adrenoceptors by co-expression with different Gα protein subunits

Intrinsic properties of alpha(2) AR ligands were investigated by measuring two distinct signalling pathways via the alpha(3A) AR protein in CHO-K1 cells: (i) a Ca2+ response mediated by a promiscuous G,x,S protein; and (ii) a pertussis toxin-resistant [S-35]GTPgammaS binding response mediated by a G(alphao)Cys(351) Ile protein. The dexefaroxan analogue RX 831003 was virtually without intrinsic activity at the wt alpha(2A) AR via a G(alpha15) protein, but induced a partial positive Ca2+ response [pEC(50): 7.79 (0.17), E-max: 38+/-1% vs (-)-adrenaline] at the mutant Thr(373L)ys alpha(2A) AR. RX 831003 displayed a similar potency (pIC(50): 7.68 (0.21) for both the wt (E-max: - 18+/-4%) and Thr(373)Lys alpha(2A), AR (E-max: -19+/-4%) inhibition of basal [S-35]GTPgammaS binding via a G(alphao)Cys(351) Ile protein. These data indicate that the alpha(2) AR ligand RX 831003 behaves as a protean agonist at the alpha(2A) AR and that its activity is highly dependent on the co-expressed G(alpha) protein subunit. (C) 2002 Published by Elsevier Science Ltd.