Small‐conductance Ca ² ⁺‐activated K⁺ channels in cardiac excitation–contraction coupling: Bridging mitochondria, sarcolemma and antiarrhythmic therapy

Small-conductance Ca²⁺-activated K⁺ (SK) channels have emerged over the past decade as compelling antiarrhythmic targets. All three isoforms, SK1, SK2 and SK3, are expressed in both atrial and ventricular cardiomyocytes, where they are exclusively gated by intracellular Ca²⁺ via constitutively bound calmodulin. Sarcolemmal SK channels uniquely translate elevations in intracellular Ca²⁺ concentration into action potential repolarization. In doing so they mitigate pro-arrhythmic disturbances in membrane potential caused by pathological spontaneous Ca²⁺ release from sarcoplasmic reticulum, thereby reducing Ca²⁺-mediated arrhythmia triggers such as early and delayed afterdepolarizations. However the role of SK channels in arrhythmogenesis is complex. Although their activation can be protective against triggered activity, additional repolarizing force under certain conditions may shorten the action potential excessively and create a substrate for re-entrant arrhythmias. Furthermore SK channels have recently been found in cardiac mitochondria, where they appear to regulate mitochondrial Ca²⁺ handling and reactive oxygen species (ROS) production, suggesting a prominent role in cardioprotection. The contribution of mitochondrial SK (mito-SK) channels to cardiac arrhythmogenesis, however, remains incompletely understood. In this review we summarize current advances in understanding the therapeutic potential of SK channels as an antiarrhythmic target, with a particular focus on the contribution of mito-SK channels to cardioprotection and mitochondrial ROS production.