The calcium and voltage clocks in sinoatrial node automaticity

Recent evidence indicates that the voltage (cyclic activation and deactivation of membrane ion channels) and Ca²⁺ clocks (rhythmic spontaneous sarcoplasmic reticulum Ca²⁺ release) jointly regulate sinoatrial node (SAN) automaticity. Since the intact SAN is a heterogeneous structure that includes multiple different cell types interacting with each other, the relative importance of the voltage and Ca²⁺ clocks for pacemaking may be variable in different regions of the SAN. Recently, we performed optical mapping in isolated and Langendorff-perfused canine right atria. We mapped the intracellular calcium (Ca_i) and membrane potentials of the intact SAN simultaneously. Using previously described criteria of the timing of the late diastolic Ca_i elevation (LDCAE) relative to the action potential upstroke to detect Ca²⁺ clock activity, we demonstrated that the sinus rate increased and the leading pacemaker shifted to the superior SAN with the robust LDCAE during β-adrenergic stimulation. We also showed that the LDCAE was caused by spontaneous diastolic SR Ca ²⁺ release and was closely related with heart rate changes. We conclude that the Ca and voltage clocks work synergistically to generate SAN automaticity.