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. 2009 Mar;296(3):H594-615. doi: 10.1152/ajpheart.01118.2008. Epub 2009 Jan 9.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Action Potentials
  • Animals
  • Biological Clocks* / drug effects
  • Calcium Signaling* / drug effects
  • Calcium-Transporting ATPases / antagonists & inhibitors
  • Computer Simulation*
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Enzyme Inhibitors / pharmacology
  • Heart Rate* / drug effects
  • Kinetics
  • Models, Cardiovascular*
  • Myocardial Contraction
  • Myocytes, Cardiac / metabolism
  • Oscillometry
  • Rabbits
  • Reproducibility of Results
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Sarcolemma / drug effects
  • Sarcolemma / enzymology
  • Sarcolemma / metabolism*
  • Sinoatrial Node / drug effects
  • Sinoatrial Node / enzymology
  • Sinoatrial Node / metabolism*
  • Sodium-Calcium Exchanger / metabolism

Substances

  • Enzyme Inhibitors
  • Ryanodine Receptor Calcium Release Channel
  • Sodium-Calcium Exchanger
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium-Transporting ATPases