Sk4 Ca2+-Activated K+ Channels Regulate Sinoatrial Node Firing Rate and Cardiac Pacing in Vivo

The sinoatrial node (SAN) controls the heart rhythm under physiological conditions. We recently showed that SK4 calcium-activated potassium channels (SK4) are important for automaticity of cardiomyocytes derived from human embryonic stem cells. Here we tested whether SK4 are expressed in adult mouse SAN and play a role in pacemaker function. TRAM-34, a selective blocker of SK4, significantly reduced the firing rate and depolarized the maximal diastolic potential in SAN cells. Western blots revealed the presence of an SK4 protein in mouse SAN. In vivo ECG recording in mice showed that intraperitoneal injection of SK4 blockers produced bradycardia and prolonged the PR interval. Mathematical modeling predicted that addition of SK4 to the model increases SAN firing rate, while its removal decreases pacemaker frequency. This work shows that SK4 play a role in SAN pacemaker function by acting at late repolarization and that they are potential therapeutic targets for treating cardiac arrhythmias.