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

Maltsev VA, Lakatta EG. Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model. Am J Physiol Heart Circ Physiol 296: H594-H615, 2009. First published January 9, 2009; doi:10.1152/ajpheart.01118.2008.-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.