title: Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model.
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.
authors.affiliation: Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825, USA.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Maltsev
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D000200:Action Potentials; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007700:Kinetics; D008955:Models, Cardiovascular; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism; D009991:Oscillometry; D011817:Rabbits; D015203:Reproducibility of Results; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012508:Sarcolemma / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D012849:Sinoatrial Node / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000252:Calcium-Transporting ATPases