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

被引:11
作者
Meini, S
Bellucci, F
Cucchi, P
Giuliani, S
Quartara, L
Giolitti, A
Zappitelli, S
Rotondaro, L
Boels, K
Maggi, CA
机构
[1] Menarini Ric SpA, Dept Pharmacol, I-50131 Florence, Italy
[2] Menarini Ric SpA, Dept Chem, I-50131 Florence, Italy
[3] Menarini Ric SpA, Dept Drug Design, I-50131 Florence, Italy
[4] Menarini Biotech, I-00040 Rome, Italy
[5] Univ Hamburg, Zentrum Mol Neurobiol, D-20246 Hamburg, Germany
关键词
GPCRs; GPCR142; FR190997; Icatibant; nonpeptide ligands; relaxin; 3; adenylyl cyclase;
D O I
10.1038/sj.bjp.0706025
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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(2)R) 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(2)R (pEC(50) = 8.6). Both effects were inhibited by the B-2 receptor antagonist Icatibant (1 muM). 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(2)R, 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 hB2R. FR190997 and relaxin 3 responses at the hB(2)R and hGPR100, respectively, were not inhibited by Icatibant (1 muM). These data indicate FR190997 and relaxin 3 as selective agonists for hB(2)R 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.
引用
收藏
页码:938 / 941
页数:4
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