STIM1 interacts with HCN4 channels to coordinate diastolic depolarization in the mouse Sinoatrial node

Cardiomyocytes in the sinoatrial node (SAN) are specialized to undergo spontaneous diastolic depolarization (DD) to create action potentials (AP) that serve as the origin of the heartbeat. Two cellular clocks govern DD: the membrane clock where ion channels contribute ionic conductance to create DD and the Ca2+ clock where rhythmic Ca2+ release from sarcoplasmic reticulum (SR) during diastole contributes pacemaking. How the membrane and Ca2+ clocks interact to synchronize and drive DD is not well understood. Here, we identified stromal interaction molecule 1 (STIM1), the activator of store operated Ca2+ entry (SOCE), in the P-cell cardiomyocytes of the SAN. Functional studies from STIM1 KO mice reveal dramatic changes in properties of AP and DD. Mechanistically, we show that STIM1 regulates the funny currents and HCN4 channels that are required to initiate DD and maintain sinus rhythm in mice. Taken together, our studies suggest that STIM1 acts as a sensor for both the Ca2+ and membrane clocks for mouse SAN for cardiac pacemaking.