NO generation by β-AR stimulation to activate CaMKII.

Ca 2+-Calmodulin (CaM) kinase II (CaMKII) activation depends predominantly on modifications of amino acids within the regulatory domain on this multidomain kinase. A number of mechanisms of activation have been described since the original mode of activation, via Ca 2+ /CaM binding and phosphorylation of a threonine residue in the regulatory domain of CaMKII, was demonstrated. In this issue of Cardiovascular Research, Gutierrez et al. 1 propose a mechanism of CaMKII activation by nitrosation. CaMKII serves as a link between β-adrenergic stimuli with subsequent changes in Ca 2+ levels to the cellular response in cardiomyocytes. CaMKII phosphorylates dozens of substrates in many cell types. When activated by binding of Ca 2+ /CaM, CaMKII subunits can autophosphorylate neighboring subunits at the Threonine287 (Thr287) within the CaMKII holoenzyme. 2 Autophosphorylation at Thr287 results in autonomous kinase activity, converting to an activation state independent of Ca 2+ /CaM binding. A number of studies have shown that CaMKII can achieve sustained activity even in the absence of phosphorylation at Thr287. Mechanisms to attain CaMKII sustained include substrate binding 3-6 , oxidation of the paired methionine residues (281/282) proximal to the Thr287 7 , and now nitrosation of cysteine residues. 1 Modifications that activate CaMKII occur primarily in the regulatory domain (Figure). These events prevent the catalytic domain from binding to the regulatory domain and allow CaMKII to retain catalytic activity for prolonged times after Ca 2+ concentrations subside. Full CaMKII activity is observed with Thr287