Synergism of coupled subsarcolemmal Ca 2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model

Victor A. Maltsev, Edward G. Lakatta

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)H594-H615
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume296
Issue number3
DOIs
StatePublished - Mar 1 2009
Externally publishedYes

Keywords

  • Calcium
  • Ion channels
  • Numerical modeling
  • Sarcoplasmic reticulum
  • Sinoatrial node cell

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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