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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    • "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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    ABSTRACT: The cardiac voltage gated Ca(2+) current (ICa) is critical to the electrophysiological properties, excitation-contraction coupling, mitochondrial energetics, and transcriptional regulation in heart. Thus, it is not surprising that cardiac ICa is regulated by numerous pathways. This review will focus on changes in ICa that occur during the cardiac action potential (AP), with particular attention to Ca(2+)-dependent inactivation (CDI), Ca(2+)-dependent facilitation (CDF) and how calmodulin (CaM) and Ca(2+)-CaM dependent protein kinase (CaMKII) participate in the regulation of Ca(2+) current during the cardiac AP. CDI depends on CaM pre-bound to the C-terminal of the L-type Ca(2+) channel, such that Ca(2+) influx and Ca(2+) released from the sarcoplasmic reticulum bind to that CaM and cause CDI. In cardiac myocytes CDI normally pre-dominates over voltage-dependent inactivation. The decrease in ICa via CDI provides direct negative feedback on the overall Ca(2+) influx during a single beat, when myocyte Ca(2+) loading is high. CDF builds up over several beats, depends on CaMKII-dependent Ca(2+) channel phosphorylation, and results in a staircase of increasing ICa peak, with progressively slower inactivation. CDF and CDI co-exist and in combination may fine-tune the ICa waveform during the cardiac AP. CDF may partially compensate for the tendency for Ca(2+) channel availability to decrease at higher heart rates because of accumulating inactivation. CDF may also allow some reactivation of ICa during long duration cardiac APs, and contribute to early afterdepolarizations, a form of triggered arrhythmias.
    Frontiers in Pharmacology 06/2014; 5:144. DOI:10.3389/fphar.2014.00144 · 3.80 Impact Factor
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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.
    Frontiers in Pharmacology 05/2014; 5:110. DOI:10.3389/fphar.2014.00110 · 3.80 Impact Factor
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    • "Using genetic tools to overexpress CaMKII or the inhibitor of CaMKII, CaMKIIN, in different cell compartments will lead to a better understanding of where CaMKII activity is required for promoting disease with particular models of stress, including MI, IR, excess catecholamine stimulation, and metabolic diseases. Conversely, CaMKII is a major contributor to myocyte Na+ homeostasis in heart failure (Wagner et al., 2006) and Na+ accumulation in heart failure was shown to influence mitochondrial Ca2+ load via enhanced NCLX-mediated Ca2+ removal (Maack et al., 2006). Thus, indirectly, cytosolic CaMKII can regulate mitochondrial Ca2+ levels. "
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    ABSTRACT: CaMKII is a newly discovered resident of mitochondria in the heart. Mitochondrial CaMKII promotes poor outcomes after heart injury from a number of pathological conditions, including myocardial infarction (MI), ischemia reperfusion (IR), and stress from catecholamine stimulation. A study using the inhibitor of CaMKII, CaMKIIN, with expression delimited to myocardial mitochondria, indicates that an underlying cause of heart disease results from the opening of the mitochondrial permeability transition pore (mPTP). Evidence from electrophysiological and other experiments show that CaMKII inhibition likely suppresses mPTP opening by reducing Ca(2+) entry into mitochondria. However, we expect other proteins involved in Ca(2+) signaling in the mitochondria are affected with CaMKII inhibition. Several outstanding questions remain for CaMKII signaling in heart mitochondria. Most importantly, how does CaMKII, without the recognized N-terminal mitochondrial targeting sequence transfer to mitochondria?
    Frontiers in Pharmacology 05/2014; 5:67. DOI:10.3389/fphar.2014.00067 · 3.80 Impact Factor
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