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

ABSTRACT: 1. Substitution of arginine by glycine at position 389, a frequent beta(1)-adrenoceptor polymorphism, reduces adenylyl cyclase stimulation by (-)-isoprenaline. beta(1)-Adrenoceptors mediate the effects of catecholamines and nonconventional partial agonists ((-)-CGP12177) through different sites. We investigated the influence of the 389 polymorphism on beta 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-beta(1)-adrenoceptors (101 fmol mg(-1) protein) or Gly389-beta(1)-adrenoceptors (94 fmol mg(-1)). 2. The affinity of beta-blockers and partial agonists, estimated from competition binding with (-)-[(125)I]-cyanopindolol, was not different for Arg389-beta(1)-adrenoceptors and Gly389-beta(1)-adrenoceptors. 3. The maximum cAMP increases by (-)-isoprenaline and (-)-CGP12177 at Gly389-beta(1)-adrenoceptors were reduced by 97 and 46%, but the potencies enhanced 2 and 0.5 log units, respectively, compared to Arg389-beta(1)-adrenoceptors. The intrinsic activity of (-)-CGP12177 with respect to the (-)-isoprenaline was 0.057 at Arg389-beta(1)-adrenoceptors and 1.05 at Gly389-beta(1)-adrenoceptors. 4. We confirm in intact CHO cells that responses to (-)-isoprenaline are markedly reduced at Gly389-beta(1)-adrenoceptors compared to Arg389-beta(1)-adrenoceptors. However, the 389 polymorphism reduces considerably less the agonist responses to (-)-CGP12177, indicating that coupling to G(s) protein is different for beta(1)-adrenoceptors activated by catecholamines than for receptors activated by nonconventional partial agonists. The affinity of beta-blockers is conserved across the Arg389Gly polymorphism.

SUBMITTER: Joseph SS

PROVIDER: S-EPMC1574932 | biostudies-literature | 2004 May

REPOSITORIES: biostudies-literature

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

Joseph S S SS Lynham J A JA Grace A A AA Colledge W H WH Kaumann A J AJ

British journal of pharmacology 20040322 1

1. Substitution of arginine by glycine at position 389, a frequent beta(1)-adrenoceptor polymorphism, reduces adenylyl cyclase stimulation by (-)-isoprenaline. beta(1)-Adrenoceptors mediate the effects of catecholamines and nonconventional partial agonists ((-)-CGP12177) through different sites. We investigated the influence of the 389 polymorphism on beta blocker affinity, as well as on the responses to (-)-isoprenaline and the nonconventional partial agonist (-)-CGP12177 on cyclic AMP levels i ...[more]

PMID: 15037517

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Project description:BackgroundThere are three turkey β-adrenoceptors: the original turkey β-adrenoceptor from erythrocytes (tβtrunc, for which the X-ray crystal structure has recently been determined), tβ3C and tβ4C-receptors. This study examined the similarities and differences between these avian receptors and mammalian receptors with regards to binding characteristics and functional high and low affinity agonist conformations.Methodology/principal findingsStable cell lines were constructed with each of the turkey β-adrenoceptors and 3H-CGP12177 whole cell binding, CRE-SPAP production and (3)H-cAMP accumulation assays performed. It was confirmed that the three turkey β-adrenoceptors are distinct from each other in terms of amino acid sequence and binding characteristics. The greatest similarity of any of the turkey β-adrenoceptors to human β-adrenoceptors is between the turkey β3C-receptor and the human β2-adrenoceptor. There are pharmacologically distinct differences between the binding of ligands for the tβtrunc and tβ4C and the human β-adrenoceptors (e.g. with CGP20712A and ICI118551). The tβtrunc and tβ4C-adrenoceptors appear to exist in at least two different agonist conformations in a similar manner to that seen at both the human and rat β1-adrenoceptor and human β3-adrenoceptors. The tβ3C-receptor, similar to the human β2-adrenoceptor, does not, at least so far, appear to exist in more than one agonist conformation.Conclusions/significanceThere are several similarities, but also several important differences, between the recently crystallised turkey β-adrenoceptor and the human β-adrenoceptors. These findings are important for those the field of drug discovery using the recently structural information from crystallised receptors to aid drug design. Furthermore, comparison of the amino-acid sequence for the turkey and human adrenoceptors may therefore shed more light on the residues involved in the existence of the secondary β-adrenoceptor conformation.

Dataset Information

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

Publications

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

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