Key result
A novel numerical model of rabbit sinoatrial node cells demonstrates that the synergism of coupled Ca2+ and membrane clocks confers robust and flexible pacemaker function over a broad rate range (1.8-4.6 Hz).
A novel numerical model demonstrates that the synergism between subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks is critical for robust and flexible sinoatrial node pacemaker function.
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No immediate clinical implications; leaves open translation of coupled clock mechanisms to human sinoatrial node disorders.
Recent experimental studies have demonstrated that sinoatrial node cells (SANC) generate spontaneous, rhythmic, local subsarcolemmal Ca(2+) releases (Ca(2+) clock), which occur during late diastolic depolarization (DD) and interact with the classic sarcolemmal voltage oscillator (membrane clock) by activating Na(+)-Ca(2+) exchanger current (I(NCX)). 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 Ca(2+) 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 Ca(2+) releases of sarcoplasmic reticulum (SR)-based Ca(2+) clock ignite rhythmic action potentials via late DD I(NCX) over much broader ranges of membrane clock parameters [e.g., L-type Ca(2+) current (I(CaL)) and/or hyperpolarization-activated ("funny") current (I(f)) conductances]. The system Ca(2+) clock includes SR and sarcolemmal Ca(2+) fluxes, which optimize cell Ca(2+) balance to increase amplitudes of both SR Ca(2+) release and late DD I(NCX) as SR Ca(2+) 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 Ca(2+) clock is unchanged or lacking. When Ca(2+) clock is disabled, the system parametric space for fail-safe SANC operation considerably shrinks: without rhythmic late DD I(NCX) ignition signals membrane clock substantially slows, becomes dysrhythmic, or halts. In conclusion, the Ca(2+) clock is a new critical dimension in SANC function. A synergism of the coupled function of Ca(2+) and membrane clocks confers fail-safe SANC operation at greatly varying rates.
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Maltsev et al. (2009) studied Sinoatrial node cell pacemaker function. Coupled subsarcolemmal Ca2+ clock and sarcolemmal voltage clock model vs. Membrane clock operating alone was evaluated on Pacemaker rate modulation and robustness. A novel numerical model of rabbit sinoatrial node cells demonstrates that the synergism of coupled Ca2+ and membrane clocks confers robust and flexible pacemaker function over a broad rate range (1.8-4.6 Hz).
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