Role of Ca 2+ in healthy and pathologic cardiac function: from normal excitation–contraction coupling to mutations that cause inherited arrhythmia

Calcium (Ca 2+ ) ions are a key second messenger involved in the rhythmic excitation and contraction of cardiomyocytes throughout the heart. Proper function of Ca 2+ -handling proteins is required for healthy cardiac function, whereas disruption in any of these can cause cardiac arrhythmias. This comprehensive review provides a broad overview of the roles of Ca 2+ -handling proteins and their regulators in healthy cardiac function and the mechanisms by which mutations in these proteins contribute to inherited arrhythmias. Major Ca 2+ channels and Ca 2+ -sensitive regulatory proteins involved in cardiac excitation–contraction coupling are discussed, with special emphasis on the function of the RyR2 macromolecular complex. Inherited arrhythmia disorders including catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, Brugada syndrome, short QT syndrome, and arrhythmogenic right-ventricular cardiomyopathy are discussed with particular emphasis on subtypes caused by mutations in Ca 2+ -handling proteins.