Sustained β1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway

Wang Wang, Weizhong Zhu, Shiqiang Wang, Dongmei Yang, Michael T. Crow, Rui Ping Xiao, Heping Cheng

Research output: Contribution to journalArticlepeer-review

Abstract

A tenet of β1-adrenergic receptor (β1AR) 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 β1AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term β1AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) β1AR 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, β1AR 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 β1AR signaling in chronic heart failure.

Original languageEnglish (US)
Pages (from-to)798-806
Number of pages9
JournalCirculation research
Volume95
Issue number8
DOIs
StatePublished - Oct 15 2004

Keywords

  • Ca/calmodulin- dependent
  • Cardiac contractility
  • Phospholamban
  • Protein kinase II
  • cAMP-dependent protein kinase
  • β-adrenergic receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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