Rhythmic Ca2+ Oscillations Drive Sinoatrial Nodal Cell Pacemaker Function to Make the Heart Tick

: Excitation‐induced Ca2+ cycling into and out of the cytosol via the sarcoplasmic reticulum (SR) Ca2+ pump, ryanodine receptor (RyR) and Na+‐Ca2+ exchanger (NCX) proteins, and modulation of this Ca2+cycling by β‐adrenergic receptor (β‐AR) stimulation, governs the strength of ventricular myocyte contraction and the cardiac contractile reserve. Recent evidence indicates that heart rate modulation and chronotropic reserve via β‐ARs also involve intracellular Ca2+ cycling by these very same molecules. Specifically, sinoatrial nodal pacemaker cells (SANC), even in the absence of surface membrane depolarization, generate localized rhythmic, submembrane Ca2+ oscillations via SR Ca2+ pumping‐RyR Ca2+ release. During spontaneous SANC beating, these rhythmic, spontaneous Ca2+ oscillations are interrupted by the occurrence of an action potential (AP), which activates L‐type Ca2+ channels to trigger SR Ca2+ release, unloading the SR Ca2+ content and inactivating RyRs. During the later part of the subsequent diastolic depolarization (DD), when Ca2+ pumped back into the SR sufficiently replenishes the SR Ca2+ content, and Ca2+‐dependent RyR inactivation wanes, the spontaneous release of Ca2+ via RyRs again begins to occur. The local increase in submembrane [Ca2+] generates an inward current via NCX, enhancing the DD slope, modulating the occurrence of the next AP, and thus the beating rate. β‐AR stimulation increases the submembrane Ca2+ oscillation amplitude and reduces the period (the time from the prior AP triggered SR Ca2+ release to the onset of the local Ca2+ release during the subsequent DD). This increased amplitude and phase shift causes the NCX current to occur at earlier times following a prior beat, promoting the earlier arrival of the next beat and thus an increase in the spontaneous firing rate. Ca2+ cycling via the SR Ca2+ pump, RyR and NCX, and its modulation by β‐AR stimulation is, therefore, a general mechanism of cardiac chronotropy and inotropy.