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 Ca ²⁺ pumped back into the SR sufficiently replenishes the SR Ca ²⁺ 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.