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

Abstract

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.

Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)

“…However, this rather small effect may have been caused by ONOO Ϫ -mediated oxidation (an effect that was ruled out in our experiments on the CaMKII␣ isoform). Indeed, in this case, the NO effect was no larger than the effect of oxidation (46), and the CaMKIIó isoform does not have a Cys residue at the position homologous to Cys-280 in CaMKII␣ (and the nitrosylation effect on CaMKII␣ autonomy demonstrated here was sensitive not only to mutation of the Cys-289 that is conserved among the isoforms, but also to mutation of the unique Cys-280).…”

“…However, in this case, CaMKII activation by NO did not appear to be through direct S-nitrosylation, as CaMKII activation (and the downstream functions) was instead dependent on PKG (47), which is activated by cGMP after NO-induced guanylyl cyclase activation (17)(18)(19). Notably, however, one of these studies showed that NO donors did also cause a direct 2.5-fold increase of CaMKIIó activity over baseline (46). However, this rather small effect may have been caused by ONOO Ϫ -mediated oxidation (an effect that was ruled out in our experiments on the CaMKII␣ isoform).…”

“…Two recent studies indicated NO-mediated regulation of CaMKII also in the heart (46,47), where CaMKII is known to have crucial pathological functions (13). However, in this case, CaMKII activation by NO did not appear to be through direct S-nitrosylation, as CaMKII activation (and the downstream functions) was instead dependent on PKG (47), which is activated by cGMP after NO-induced guanylyl cyclase activation (17)(18)(19).…”

S-Nitrosylation Induces Both Autonomous Activation and Inhibition of Calcium/Calmodulin-dependent Protein Kinase II δ

“…Moreover, CaMKII␦ activity is enhanced by NO donors (14), there is evidence that myocyte CaMKII can be nitrosylated (11,12), and several S-nitrosylation sites have been predicted by consensus modeling. Therefore, CaMKII␦ may be directly modified by NO (12).…”

“…For example, ␤-adrenergic stimulation activates CaMKII␦ in part through an NO synthase-dependent pathway (11), which increases the sarcoplasmic reticulum Ca 2ϩ leak via ryanodine receptors (11,12,13). Moreover, CaMKII␦ activity is enhanced by NO donors (14), there is evidence that myocyte CaMKII can be nitrosylated (11,12), and several S-nitrosylation sites have been predicted by consensus modeling. Therefore, CaMKII␦ may be directly modified by NO (12).…”