Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels

Abstract

In heart failure (HF), Ca2+/calmodulin kinase II (CaMKII) expression is increased. Altered Ne channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na+ channel gating, in part perhaps via CaMKII. We investigated effects of adenovirus-mediated (acute) and Tg (chronic) overexpression of cytosolic CaMKII delta(C) on Na+ current (IN) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKII delta(C) overexpression shifted voltage dependence of Na+ channel availability by -6 mV (P < 0.05), and the shift was Ca2+ dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2-related inhibitory peptide [AIP] or KN93). CaMKII delta(C) markedly increased persistent (late) inward INa and intracellular Na+ concentration (as measured by the Na+ indicator sodium-binding benzofuran isophthalate [SBFI]), which was prevented by CaMKII inhibition in the case of acute CaMKII delta(C) overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na+ channels. In vivo, transgenic CaMKII delta(C) overexpression prolonged QRS duration and repolarization (QT intervals), decreased effective refractory periods, and increased the propensity to develop VT. We conclude that CaMKII associates with and phosphorylates cardiac Na+ channels. This alters INa gating to reduce availability at high heart rate, while enhancing late INa (which could prolong action potential duration). In mice, enhanced CaMKII delta(C) activity predisposed to VT. Thus, CaMKII-dependent regulation of Na+ channel function may contribute to arrhythmogenesis in HF.