Published online before print July 7, 2005, doi: 10.1161/01.RES.0000176764.38934.86
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© 2005 American Heart Association, Inc.
Cellular Biology |
Heterodimerization of ß1- and ß2-Adrenergic Receptor Subtypes Optimizes ß-Adrenergic Modulation of Cardiac Contractility
From the Laboratory of Cardiovascular Science (W.-Z.Z., K.C., S.Z., D.Y., E.G.L., H.C., R.-P.X.), Gerontology Research Center, National Institute on Aging, Baltimore, Md; Centre de recherche (C.L.), Institut de Cardiologie de Montréal, Canada; Département de biochimie (C.L., T.E.H., M.B.), Université de Montréal, Canada; and the Institute of Molecular Medicine (R.-P.X.), Peking University, Beijing, China.
Correspondence to Dr Rui-Ping Xiao, Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail xiaor{at}grc.nia.nih.gov
Intermolecular interactions between members of both similar and divergent G protein-coupled receptor subfamilies have been shown in various experimental systems. Here, we demonstrate heterodimerization of predominant ß-adrenergic receptor (ßAR) subtypes expressed in the heart, ß1AR, and ß2AR, and its physiological relevance. In intact adult-mouse cardiac myocytes lacking native ß1AR and ß2AR, coexpression of both ßAR subtypes led to receptor heterodimerization, as evidenced by their coimmunoprecipitation, colocalization at optical resolution, and markedly increased binding affinity for subtype-selective ligands. As a result, the dose-response curve of myocyte contraction to ßAR agonist stimulation with isoproterenol (ISO) was shifted leftward by 
1.5 orders of magnitude, and the response of cellular cAMP formation to ISO was enhanced concomitantly, indicating that intermolecular interactions of ßAR subtypes resulted in sensitization of these receptors in response to agonist stimulation. In contrast, the presence of ß1AR greatly suppressed ligand-independent spontaneous activity of coexisting ß2ARs. Thus, heterodimerization of ß1AR and ß2AR in intact cardiac myocytes creates a novel population of ßARs with distinct functional and pharmacological properties, resulting in enhanced signaling efficiency in response to agonist stimulation while silencing ligand-independent receptor activation, thereby optimizing ß-adrenergic modulation of cardiac contractility.
Key Words: receptor dimerization • ß-adrenergic receptor • G protein-coupled receptors • cardiac contractility • ligand binding
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