Bradykinin B 2 and GPR100 receptors: A paradigm for receptor signal transduction pharmacology

Abstract

The aim of the present report was to investigate the ligand selectivity of the human orphan G-protein-coupled receptor GPR100 (hGPR100), recently identified as a novel bradykinin (BK) receptor, as compared with that of the human B 2 receptor (hB 2R) stably transfected in Chinese hamster ovary cells. BK was able to inhibit the cAMP production induced by forskolin with a potency 100-fold lower at the hGPR100 (pEC 50=6.6) than that measured at the hB 2R (pEC 50=8.6). Both effects were inhibited by the B 2 receptor antagonist Icatibant (1 μM). The nonpeptide B 2 receptor agonist FR190997 (8-[2,6-dichloro-3-[N- methylcarbamoyl)cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methyl-4-(2- pyridylmethoxy)quinoline) did inhibit the forskolin-induced cAMP production (pEC 50=7.7) at the hB 2R, whereas it was not able to exert any effect at the hGPR100. The human insulin-like peptide relaxin 3 did inhibit the cAMP production at the hGPR100 (pEC 50=7.3) at a greater extent than BK, and was devoid of any effect at the hB 2R. FR190997 and relaxin 3 responses at the hB 2R and hGPR100, respectively, were not inhibited by Icatibant (1 μM). These data indicate FR190997 and relaxin 3 as selective agonists for hB 2R and hGPR100, respectively, and support the concept that different agonists may specifically bias the conformational states of a receptor to result in a final common G protein coupling, which is differentially recognized by antagonists.