Molecular basis of catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant arrhythmia syndrome linked to mutations in the cardiac ryanodine receptor (RyR2) and calsequestrin (CASQ2). RyR2 and CASQ2 are parts of the multimolecular Ca2+ release channel complex that is present on the sarcoplasmic reticulum (SR) to support myocyte Ca2+ cycling and contractile activity. Whereas RyR2 operates as a Ca2+ release channel, the SR Ca2+ binding protein CASQ2 plays a dual role by serving as a SR Ca2+ buffer and by regulating RyR2 function. Essential to stable Ca2+ cycling, SR luminal Ca2+-dependent control of RyR2 activity by CASQ2 contributes to RyR2 deactivation and to the development of a temporary refractory state that occurs after each Ca2+ release. Accumulating evidence suggests that the CPVT mutations act by reducing the extent and shortening the duration of Ca2+ signaling refractoriness, thereby promoting untimely SR Ca2+ release and arrhythmogenic delayed afterdepolarizations in cardiac myocytes. Similar mechanisms may apply to arrhythmias during various conditions, including heart failure and ischemic heart disease, associated with acquired defects in components of the Ca2+ release channel complex.