PKA phosphorylation underlies functional recruitment of sarcolemmal SK2 channels in ventricular myocytes from hypertrophic hearts

Abstract Key points summary Small‐conductance Ca2+‐activated K+ (SK) channels expressed in ventricular myocytes are dormant in health yet become functional in cardiac disease. SK channels are voltage independent and their gating is controlled by intracellular [Ca2+] in a biphasic manner. Submicromolar [Ca2+] activates the channel via constitutively‐bound calmodulin, while higher [Ca2+] exerts inhibitory effect during depolarization. Using a rat model of cardiac hypertrophy induced by thoracic aortic banding, we found that functional upregulation of SK2 channels in hypertrophic rat ventricular cardiomyocytes is driven by PKA phosphorylation. Using site‐directed mutagenesis, we identified Serine‐465 as the site to confer PKA‐dependent effects on SK2 channel function. PKA phosphorylation attenuates ISK rectification by reducing the Ca2+/voltage‐dependent inhibition of SK channels without changing their sensitivity to activating submicromolar [Ca2+]i. This mechanism underlies the functional recruitment of SK channels not only in cardiac disease but also in normal physiology, contributing to repolarization under conditions of enhanced adrenergic drive.