Human heart beta-adrenoceptors: beta(1)-adrenoceptor diversification through 'affinity states' and polymorphism

Molenaar, P., Chen, L., Semmler, A. B. T., Parsonage, W. A. and Kaumann, A. J. (2007) Human heart beta-adrenoceptors: beta(1)-adrenoceptor diversification through 'affinity states' and polymorphism. Clinical And Experimental Pharmacology And Physiology, 34 10: 1020-1028. doi:10.1111/j.1440-1681.2007.04730.x

Author Molenaar, P.
Chen, L.
Semmler, A. B. T.
Parsonage, W. A.
Kaumann, A. J.
Title Human heart beta-adrenoceptors: beta(1)-adrenoceptor diversification through 'affinity states' and polymorphism
Journal name Clinical And Experimental Pharmacology And Physiology   Check publisher's open access policy
ISSN 0305-1870
Publication date 2007-10
Sub-type Article (original research)
DOI 10.1111/j.1440-1681.2007.04730.x
Volume 34
Issue 10
Start page 1020
End page 1028
Total pages 9
Place of publication Oxford, England
Publisher Blackwell Publishing
Language eng
Subject 0606 Physiology
1115 Pharmacology and Pharmaceutical Sciences
Abstract In atrium and ventricle from failing and non-failing human hearts, activation of beta(1)- or beta(2)-adrenoceptors causes increases in contractile force, hastening of relaxation, protein kinase A-catalysed phosphorylation of proteins implicated in the hastening of relaxation, phospholamban, troponin I and C-protein, consistent with coupling of both beta(1)- and beta(2)-adrenoceptors to stimulatory G(sa)-protein but not inhibitory G(ia)-protein. Two 'affinity states', namely beta(1H) and beta(1L), of the beta(1)-adrenoceptor exist. In human heart, noradrenaline elicits powerful increases in contractile force and hastening of relaxation. These effects are blocked with high affinity by beta-adenoceptor antagonists, including propranolol, (-)-pindolol, (-)-CGP 12177 and carvedilol. Some beta-blockers, typified by (-)-pindolol and (-)-CGP 12177, not only block the receptor, but also activate it, albeit at much higher concentrations (approximately 2 log units) than those required to antagonize the effects of catecholamines. In human heart, both (-)-CGP 12177 and (-)-pindolol increase contractile force and hasten relaxation. However, the involvement of the beta(1)-adrenoceptor was not immediately obvious because (-)-pindolol- and (-)-CGP 12177-evoked responses were relatively resistant to blockade by (-)-propranolol. Abrogation of cardiostimulant effects of (-)-CGP 12177 in beta(1)-/beta(2)-adrenoceptor double-knockout mice, but not beta(2)-adrenoceptor-knockout mice, revealed an obligatory role of the beta(1)-adrenoceptor. On the basis of these results, two 'affinity states' have been designated, the beta(1H)- and beta(1L)-adrenoceptor, where the beta(1H)-adrenoceptor is activated by noradrenaline and blocked with high affinity by beta-blockers and the beta(1L)-adrenoceptor is activated by drugs such as (-)-CGP 12177 and (-)-pindolol and blocked with low affinity by beta-blockers such as (-)-propranolol. The beta(1H)- and beta(1L)-adrenoceptor states are consistent with high- and low-affinity binding sites for (-)-[H-3]-CGP 12177 radioligand binding found in cardiac muscle and recombinant beta(1)-adrenoceptors. There are two common polymorphic locations of the beta(1)-adrenoceptor, at amino acids 49 (Ser/Gly) and 389 (Arg/Gly). Their existence has raised several questions, including their role in determining the effectiveness of heart failure treatment with beta-blockers. We have investigated the effect of long-term maximally tolerated carvedilol administration (> 1 year) on left ventricular ejection fraction (LVEF) in patients with non-ischaemic cardiomyopathy (mean left ventricular ejection fraction 23 +/- 7%; n = 135 patients). The administration of carvedilol improved LVEF to 37 +/- 13% (P < 0.005); however, the improvement was variable, with 32% of patients showing pound 5% improvement. Upon segregation of patients into Arg389Gly-beta(1)-adrenoceptors, it was found that carvedilol caused a greater increase in left ventricular ejection faction in patients carrying the Arg389 allele with Arg389Arg > Arg389Gly > Gly389Gly.
Keyword Pharmacology & Pharmacy
beta(1)-adrenoceptor affinity states
beta-adrenoceptor-G(s alpha)-protein coupling
beta-adrenoceptor polymorphism
(-)-CGP 12177
hastening of relaxation
human heart beta-adrenoceptors
human heart failure
phosphodiesterase enzymes
Idiopathic Dilated Cardiomyopathy
Human Atrial Myocardium
Adrenergic-receptor Polymorphisms
Cardiac-insufficiency Bisoprolol
Ventricular Myocardium
Phospholamban Phosphorylation
Autoradiographic Localization
Q-Index Code C1
Additional Notes Annual Scientific Meeting of ASCEPT 2006 -- Published Online: 15 Aug 2007

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
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Created: Mon, 18 Feb 2008, 14:49:34 EST