期刊
CIRCULATION RESEARCH
卷 95, 期 8, 页码 798-806出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000145361.50017.aa
关键词
beta(1)-adrenergic receptor; Ca2+/calmodulin-dependent protein kinase II; cAMP-dependent protein kinase; cardiac contractility; phospholamban
A tenet of beta(1)-adrenergic receptor (beta(1)AR) 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 beta(1)AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term beta(1)AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) beta(1)AR 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 ((16)Ser) to CaMKII site ((17)Thr). Thus, beta(1)AR 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 beta(1)AR signaling in chronic heart failure.
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