Ca/Calmodulin-dependent protein kinase II regulates cardiac Na+ channels

Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany.
Journal of Clinical Investigation (Impact Factor: 13.22). 01/2007; 116(12):3127-38. DOI: 10.1172/JCI26620
Source: PubMed


In heart failure (HF), Ca(2+)/calmodulin kinase II (CaMKII) expression is increased. Altered Na(+) 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 CaMKIIdelta(C) on Na(+) current (I(Na)) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKIIdelta(C) overexpression shifted voltage dependence of Na(+) channel availability by -6 mV (P < 0.05), and the shift was Ca(2+) dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2-related inhibitory peptide [AIP] or KN93). CaMKIIdelta(C) markedly increased persistent (late) inward I(Na) 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 CaMKIIdelta(C) overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na(+) channels. In vivo, transgenic CaMKIIdelta(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 I(Na) gating to reduce availability at high heart rate, while enhancing late I(Na) (which could prolong action potential duration). In mice, enhanced CaMKIIdelta(C) activity predisposed to VT. Thus, CaMKII-dependent regulation of Na(+) channel function may contribute to arrhythmogenesis in HF.

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    • "Binding sites for Ca 2+ and the Ca 2+ -binding protein calmodulin are present at the carboxyl terminus[65,66], allowing modulation of channel function[67,68]. Ca 2+ /calmodulin-dependent Kinase II phosphorylates the sodium channel, causing a negative shift in the voltage-dependence of steady-state inactivation without altering the voltage-dependence of steady-state activation or the peak I Na[69]. I Na consists mainly of a tetrodotoxin-insensitive component, attributable to the cardiac isoform Na V 1.5[50,70,71]. "
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    ABSTRACT: Ventricular arrhythmias arise from disruptions in the normal orderly sequence of electrical activation and recovery of the heart. They can be categorized into disorders affecting predominantly cellular depolarization or repolarization, or those involving action potential (AP) conduction. This article briefly discusses the factors causing conduction abnormalities in the form of unidirectional conduction block and reduced conduction velocity (CV). It then examines the roles that sodium channels and gap junctions play in AP conduction. Finally, it synthesizes experimental results to illustrate molecular mechanisms of how abnormalities in these proteins contribute to such conduction abnormalities and hence ventricular arrhythmogenesis, in acquired pathologies such as acute ischaemia and heart failure, as well as inherited arrhythmic syndromes.
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    • "They also showed that the CaMKII-Ca2+-CaMKII feedback is enhanced by β-adrenergic stimulation (which further enhances Ca2+ signal). We recently extended their work, by studying the synergy of Na+ handling with Ca2+ and CaMKII signaling, since CaMKII hyperactivity in HF has also been associated with late INa and intracellular [Na+] ([Na+]i) overload (Wagner et al., 2006; Grandi and Herren, 2014). We found that a significant gain in [Na+]i (~ 3–4 mM), which is what happens in HF (Despa et al., 2002), induces an increase in Ca2+ and consequent Ca2+-dependent CaMKII activation, which in turn enhances Na+ and Ca2+ signals, leading to a pro-arrhythmic condition. "
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    Full-text · Article · Jun 2014 · Frontiers in Pharmacology
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    • "Murine models of heart failure, CaMKII hyperactivity (overexpression ), and CaMKII regulation of RyR2 have provided a wealth of information describing how CaMKII contributes to both arrhythmogenesis and disease progression in cardiomyopathy . Cardiac restricted overexpression of CaMKIIδ C in the mouse leads to heart failure, inducible arrhythmia, and premature death (Zhang et al., 2003; Wagner et al., 2006). In these mice, acute inhibition of CaMKII (via KN-93) prevents catecholaminergic arrhythmia in vivo, and RyR2 dysfunction was implicated in this arrhymogenic mechanism (Figure 3, mechanism 3) by a substantial and CaMKII-dependent increase in SR Ca 2+ leak, elevated diastolic Ca 2+ , and DADs during Iso challenge (Sag et al., 2009). "
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    ABSTRACT: Calcium/calmodulin-dependent protein kinase II (CaMKII) activity has been shown to contribute to arrhythmogenesis in a remarkably broad range of cardiac pathologies. Several of these involve significant structural and electrophysiologic remodeling, whereas others are due to specific channelopathies, and are not typically associated with arrhythmogenic changes to protein expression or cellular and tissue structure. The ability of CaMKII to contribute to arrhythmia across such a broad range of phenotypes suggests one of two interpretations regarding the role of CaMKII in cardiac arrhythmia: (1) some CaMKII-dependent mechanism is a common driver of arrhythmia irrespective of the specific etiology of the disease, or (2) these different etiologies expose different mechanisms by which CaMKII is capable of promoting arrhythmia. In this review, we dissect the available mechanistic evidence to explore these two possibilities and discuss how the various molecular actions of CaMKII promote arrhythmia in different pathophysiologic contexts.
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