CaMKII as a novel therapeutic target for lethal ventricular tachyarrhythmias

Abstract

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional kinase that can phosphorylate proteins involved in regulating Ca²⁺-storage and -release, transcription factors, and ion channels. While CaMKII is reversibly activated upon beat-to-beat elevation of intracellular Ca²⁺ (Ca²⁺-dependent form), it is converted into a constitutively-active Ca²⁺-independent form by cardiac stressors, such as fast activation rate, chronic adrenergic stimulation and oxidative stress. Moreover, there is a synergetic interaction between upregulated CaMKII and functional changes in Na⁺-channels (enhanced late Na⁺-current) and ryanodine receptor channels (increased diastolic sarcoplasmic reticulum Ca²⁺-leak), further augmenting persistent Ca²⁺-independent activity via a proarrhythmic CaMKII-Na⁺-Ca²⁺ positive feedback loop. The CaMKII overactivity is connected to a variety of cardiac diseases including heart failure, myocardial infarction, ischemia/reperfusion and arrhythmias. Here we review the pathophysiological roles of CaMKII, together with our findings from an experimental model of electrical storm featuring repetitive defibrillator-firings for recurrent ventricular tachyarrhythmias.