Markedly reduced effects of (-)-isoprenaline but not of (-)-CGP12177 and unchanged affinity of beta-blockers at Gly389-beta1-adrenoceptors compared to Arg389-beta1-adrenoceptors.

1: Substitution of arginine by glycine at position 389, a frequent ß1-adrenoceptor polymorphism, reduces adenylyl cyclase stimulation by (-)-isoprenaline. ß1-Adrenoceptors mediate the effects of catecholamines and nonconventional partial agonists ((-)-CGP12177) through different sites. We investigated the influence of the 389 polymorphism on ß blocker affinity, as well as on the responses to (-)-isoprenaline and the nonconventional partial agonist (-)-CGP12177 on cyclic AMP levels in CHO cells expressing recombinant Arg389-ß1-adrenoceptors (101?fmol?mg-1 protein) or Gly389-ß1-adrenoceptors (94?fmol?mg-1). 2: The affinity of ß-blockers and partial agonists, estimated from competition binding with (-)-[125I]-cyanopindolol, was not different for Arg389-ß1-adrenoceptors and Gly389-ß1-adrenoceptors. 3: The maximum cAMP increases by (-)-isoprenaline and (-)-CGP12177 at Gly389-ß1-adrenoceptors were reduced by 97 and 46%, but the potencies enhanced 2 and 0.5 log units, respectively, compared to Arg389-ß1-adrenoceptors. The intrinsic activity of (-)-CGP12177 with respect to the (-)-isoprenaline was 0.057 at Arg389-ß1-adrenoceptors and 1.05 at Gly389-ß1-adrenoceptors. 4: We confirm in intact CHO cells that responses to (-)-isoprenaline are markedly reduced at Gly389-ß1-adrenoceptors compared to Arg389-ß1-adrenoceptors. However, the 389 polymorphism reduces considerably less the agonist responses to (-)-CGP12177, indicating that coupling to Gs protein is different for ß1-adrenoceptors activated by catecholamines than for receptors activated by nonconventional partial agonists. The affinity of ß-blockers is conserved across the Arg389Gly polymorphism.British Journal of Pharmacology (2004) 142, 51-56. doi:10.1038/sj.bjp.0705753 [ABSTRACT FROM AUTHOR]