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Calmodulin and CaMKII signaling in the heart

D.M. Bers, Department of Pharmacology, University of California Davis, Davis, CA 95616, USA.

Ca is essential in cardiac electrophysiology, contraction, energetics and nuclear transcription. Calmodulin (CaM) and Ca/CaM-dependent protein kinase (CaMKII) are also important mediators of Ca signaling in myocytes. CaMKII can phosphorylate and modulate function of Na, Ca and K channels, ryanodine receptor (RyR) and IP3 receptor channels, the phospholamban-SERCA complex and myofilaments. Some of these pathways may contribute to decreased cardiac function and enhanced propensity for arrhythmias in hypertrophy and heart failure (HF). Since CaMKII expression and activation state is increased in HF, these pathways may be important in contributing to the development and consequences of HF and may represent important therapeutic targets. CaMKII effects on cardiac Na channels and RyRs may be particularly important in HF and arrhythmias, and these acquired CaMKII-dependent effects can recapitulate genetic mutations in these channels that are associated with long QT (LQT), Brugada syndromes and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). In particular CaMKII can phosphorylate NaV1.5 and cause both enhanced late INa (as observed in LQT3) and also loss of Na channel availability (as observed in NaV1.5 mutants linked to Brugada and short QT syndromes) which the outcome dependent on heart rate. RyR phosphorylation by CaMKII increase diastolic sarcoplasmic reticulum (SR) Ca leak (as occurs in CPVT-linked mutations in Ryr2 and calsequestrin 2). This altered RyR gating can lead to increase delayed afterdepolarizations (DADs) and serve as a source of triggered arrhythmias as well as cause reduced SR Ca content available for release in HF myocytes. Thus, CaMKII activation in HF and arrhythmogenic conditions can mediate acquired forms of cardiac arrhythmias and contractile dysfunction in pathologic conditions.

CaM, calcineurin and CaMKII are also involved in nuclear transcriptional regulation in pathways that involve histone deacetylases (HDACs) and NFATs, and these may contribute to the development of cardiac hypertrophy, failure and arrhythmias. Indeed, CaMKII-dependent pathways may alter the expression levels of key ion transporters, channels and regulators that reinforce the heart failure phenotype. IP3 receptors and Ca store-dependent CaM and CaMKII/PKD activation are involved in regulating HDAC5 nuclear translocation. Nuclear HDAC5 binds to MEF2 and suppresses MEF2-driven transcription, whereas HDAC5 nuclear export relieves this and thereby activates hypertrophic gene transcription. Remarkably, this Ca-dependent pathway is insensitive to global Ca transients at each heartbeat, and is functionally insulated from Ca involved in EC coupling. Thus myocytes can distinguish simultaneous local and global Ca signals involved in contractile activation from those targeting gene expression. Thus Ca and CaMKII signaling in cardiac myocytes can mediate many acute effects (in seconds to hours) that influence cardiac electrophysiology and contractile function, and also on a longer time scale (tens of minutes to days) influence gene expression and contribute to cellular and molecular remodeling.