Bradykinin B2 and GPR100 receptors: a paradigm for receptor signal transduction pharmacology

• Published in: British journal of pharmacology Vol. 143; no. 8; pp. 938 - 941
• Main Authors: Meini, Stefania, Bellucci, Francesca, Cucchi, Paola, Giuliani, Sandro, Quartara, Laura, Giolitti, Alessandro, Zappitelli, Sabrina, Rotondaro, Luigi, Boels, Katrin, Maggi, Carlo Alberto
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2004
• Subjects: adenylyl cyclase; Animals; Bradykinin - metabolism; Bradykinin - pharmacology; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; FR190997; GPCR142; GPCRs; Humans; Icatibant; nonpeptide ligands; Receptor, Bradykinin B2 - metabolism; Receptors, Bradykinin - physiology; relaxin 3; Signal Transduction - drug effects; Signal Transduction - physiology; Special Reports
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706025

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 B2 receptor (hB2R) 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 (pEC50=6.6) than that measured at the hB2R (pEC50=8.6). Both effects were inhibited by the B2 receptor antagonist Icatibant (1 μM). The nonpeptide B2 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 (pEC50=7.7) at the hB2R, 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 (pEC50=7.3) at a greater extent than BK, and was devoid of any effect at the hB2R. FR190997 and relaxin 3 responses at the hB2R and hGPR100, respectively, were not inhibited by Icatibant (1 μM). These data indicate FR190997 and relaxin 3 as selective agonists for hB2R 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. British Journal of Pharmacology (2004) 143, 938–941. doi:10.1038/sj.bjp.0706025