Recent experimental studies have demonstrated that sinoatrial node cells (SANC) generate spontaneous, rhythmic, local subsarcolemmal Ca2+ releases (Ca2+ clock), which occur during late diastolic depolarization (DD) and interact with the classic sarcolemmal voltage oscillator (membrane clock) by activating Na+-Ca2+ exchanger current ( INCX). This and other interactions between clocks, however, are not captured by existing essentially membrane-delimited cardiac pacemaker cell numerical models. Using wide-scale parametric analysis of classic formulations of membrane clock and Ca2+ cycling, we have constructed and initially explored a prototype rabbit SANC model featuring both clocks. Our coupled oscillator system exhibits greater robustness and flexibility than membrane clock operating alone. Rhythmic spontaneous Ca2+ releases of sarcoplasmic reticulum (SR)-based Ca2+ clock ignite rhythmic action potentials via late DD INCX over much broader ranges of membrane clock parameters [e.g., L-type Ca2+ current ( ICaL) and/or hyperpolarization-activated (“funny”) current ( If) conductances]. The system Ca2+ clock includes SR and sarcolemmal Ca2+ fluxes, which optimize cell Ca2+ balance to increase amplitudes of both SR Ca2+ release and late DD INCX as SR Ca2+ pumping rate increases, resulting in a broad pacemaker rate modulation (1.8–4.6 Hz). In contrast, the rate modulation range via membrane clock parameters is substantially smaller when Ca2+ clock is unchanged or lacking. When Ca2+ clock is disabled, the system parametric space for fail-safe SANC operation considerably shrinks: without rhythmic late DD INCX ignition signals membrane clock substantially slows, becomes dysrhythmic, or halts. In conclusion, the Ca2+ clock is a new critical dimension in SANC function. A synergism of the coupled function of Ca2+ and membrane clocks confers fail-safe SANC operation at greatly varying rates.
Adherens Junction Engagement Regulates Functional Patterning of the Cardiac Pacemaker Cell Lineage
