Sustained β 1 -Adrenergic Stimulation Modulates Cardiac Contractility by Ca 2+ /Calmodulin Kinase Signaling Pathway

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Abstract
A tenet of β 1 -adrenergic receptor (β 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 Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) in β 1 AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term β 1 AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) β 1 AR stimulation with norepinephrine similarly enhanced cell contraction and Ca 2+ 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 Ca 2+ cycling regulatory protein, was shifted from its PKA site ( 16 Ser) to CaMKII site ( 17 Thr). Thus, β 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 β 1 AR signaling in chronic heart failure.

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