Markedly reduced effects of (−)‐isoprenaline but not of (−)‐CGP12177 and unchanged affinity of β ‐blockers at Gly389‐ β 1 ‐adrenoceptors compared to Arg389‐ β 1 ‐adrenoceptors

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