Evidence for protean agonism of RX 831003 at alpha 2A-adrenoceptors by co-expression with different G alpha protein subunits.
Intrinsic properties of alpha(2) AR ligands were investigated by measuring two distinct signalling pathways via the alpha(2A) AR protein in CHO-K1 cells: (i) a Ca(2+) response mediated by a promiscuous G(alpha 15) protein; and (ii) a pertussis toxin-resistant [(35)S]GTP gamma S binding response mediated by a G(alpha o)Cys(351)Ile protein. The dexefaroxan analogue RX 831003 was virtually without intrinsic activity at the wt alpha(2A) AR via a G(alpha 15) protein, but induced a partial positive Ca(2+) 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 [(35)S]GTP gamma S binding via a G(alpha o)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.
Pauwels
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PJ
Centre de Recherche Pierre Fabre, Department of Cellular and Molecular Biology, 17, avenue Jean Moulin, 81106 Castres Cedex, France. peter.pauwels@pierre-fabre.com
Rauly
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Wurch
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Colpaert
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D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology; D020962:Heterotrimeric GTP-Binding Proteins / Q000096:biosynthesis*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018341:Receptors, Adrenergic, alpha-2 / Q000096:biosynthesis* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
C547768:ADRA2A protein, human; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D001578:Benzopyrans; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020962:Heterotrimeric GTP-Binding Proteins; C451723:dexefaroxan