Published online before print September 16, 2004, doi: 10.1161/01.RES.0000145361.50017.aa
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© 2004 American Heart Association, Inc.
Cellular Biology |
Sustained ß1-Adrenergic Stimulation Modulates Cardiac Contractility by Ca2+/Calmodulin Kinase Signaling Pathway
From the Laboratory of Cardiovascular Sciences (W.W., W.Z., S.W., D.Y., R.-P.X., H.C), National Institute on Aging, National Institutes of Health; Department of Medicine (M.T.C.), Johns Hopkins University, School of Medicine, Baltimore, Md; and The Institute of Molecular Medicine (R.-P.X., H.C.), Peking University, Beijing, China.
Correspondence to Heping Cheng, PhD, Laboratory of Cardiovascular Sciences, NIA, NIH, Baltimore, MD 21224. E-mail chengp{at}grc.nia.nih.gov
A tenet of ß1-adrenergic receptor (ß1AR) signaling is that stimulation of the receptor activates the adenylate cyclase-cAMP-protein kinase A (PKA) pathway, resulting in positive inotropic and relaxant effects in the heart. However, recent studies have suggested the involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in ß1AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term ß1AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) ß1AR stimulation with norepinephrine similarly enhanced cell contraction and Ca2+ transients, in contrast to anticipated receptor desensitization. More importantly, the sustained responses were largely PKA-independent, and were sensitive to specific CaMKII inhibitors or adenoviral expression of a dominant-negative CaMKII mutant. Biochemical assays revealed that a progressive and persistent CaMKII activation was associated with a rapid desensitization of the cAMP/PKA signaling. Concomitantly, phosphorylation of phospholamban, an SR Ca2+ cycling regulatory protein, was shifted from its PKA site (16Ser) to CaMKII site (17Thr). Thus, ß1AR stimulation activates dual signaling pathways mediated by cAMP/PKA and CaMKII, the former undergoing desensitization and the latter exhibiting sensitization. This finding may bear important etiological and therapeutical ramifications in understanding ß1AR signaling in chronic heart failure.
Key Words: ß1-adrenergic receptor • Ca2+/calmodulin-dependent protein kinase II • cAMP-dependent protein kinase • cardiac contractility • phospholamban
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