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Synergism of coupled subsarcolemmal Ca²⁺ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model

Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland

Submitted 24 October 2008 ; accepted in final form 4 January 2009

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 (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 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 I_NCX over much broader ranges of membrane clock parameters [e.g., L-type Ca²⁺ current (I_CaL) and/or hyperpolarization-activated ("funny") current (I_f) 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 I_NCX 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 I_NCX 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.

calcium; sarcoplasmic reticulum; ion channels; numerical modeling; sinoatrial node cell

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