January 10, 2009Open Access
Synergism of coupled subsarcolemmal Ca2+clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model
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).
Structured PICO
P
Population
Prototype rabbit sinoatrial node cell (SANC) numerical model
I
Intervention
Coupled oscillator system featuring both sarcolemmal voltage oscillator (membrane clock) and subsarcolemmal Ca2+ clock
C
Comparator
Membrane clock operating alone (Ca2+ clock disabled or unchanged)
O
Outcome
Pacemaker function robustness, flexibility, and rate modulation rangesurrogate
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.
Abstract
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.