Gutierrez, Daniel A. , FERNANDEZ TENORIO, MIGUEL, Ogrodnik, Jakob , Niggli, Ernst
No
Cardiovasc. Res.
Article
Científica
5.808
2.832
01/12/2013
000327398400008
During -adrenergic receptor (-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 -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 -AR stimulation in single cardiomyocytes in diastolic conditions. Confocal imaging revealed that -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. -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.
CaMKII; Ca sparks; Ca waves; NO-synthase