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Cardiovasc Res. 2013 Dec 1;100(3):392-401. doi: 10.1093/cvr/cvt201. Epub 2013 Aug 20.

NO-dependent CaMKII activation during β-adrenergic stimulation of cardiac muscle.

Author information

1
Department of Physiology, University of Bern, Bühlplatz 5, CH-3012 Bern, Switzerland.

Abstract

AIMS:

During β-adrenergic receptor (β-AR) stimulation, phosphorylation of cardiomyocyte ryanodine receptors by protein kinases may contribute to an increased diastolic Ca(2+) spark frequency. Regardless of prompt activation of protein kinase A during β-AR stimulation, this appears to rely more on activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), by a not yet identified signalling pathway. The goal of the present study was to identify and characterize the mechanisms which lead to CaMKII activation and elevated Ca(2+) spark frequencies during β-AR stimulation in single cardiomyocytes in diastolic conditions.

METHODS AND RESULTS:

Confocal imaging revealed that β-AR stimulation increases endogenous NO production in cardiomyocytes, resulting in NO-dependent activation of CaMKII and a subsequent increase in diastolic Ca(2+) spark frequency. These changes of spark frequency could be mimicked by exposure to the NO donor GSNO and were sensitive to the CaMKII inhibitors KN-93 and AIP. In vitro, CaMKII became nitrosated and its activity remained increased independent of Ca(2+) in the presence of GSNO, as assessed with biochemical assays.

CONCLUSIONS:

β-AR stimulation of cardiomyocytes may activate CaMKII by a novel direct pathway involving NO, without requiring Ca(2+) transients. This crosstalk between two established signalling pathways may contribute to arrhythmogenic diastolic Ca(2+) release and Ca(2+) waves during adrenergic stress, particularly in combination with cardiac diseases. In addition, NO-dependent activation of CaMKII is likely to have repercussions in many cellular signalling systems and cell types.

KEYWORDS:

Ca sparks; Ca waves; CaMKII; NO-synthase

PMID:
23963842
DOI:
10.1093/cvr/cvt201
[Indexed for MEDLINE]
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