title: Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells.
abstract: Recent evidence indicates that the spontaneous action potential (AP) of isolated sinoatrial node cells (SANCs) is regulated by a system of stochastic mechanisms embodied within two clocks: ryanodine receptors of the "Ca(2+) clock" within the sarcoplasmic reticulum, spontaneously activate during diastole and discharge local Ca(2+) releases (LCRs) beneath the cell surface membrane; clock crosstalk occurs as LCRs activate an inward Na(+)/Ca(2+) exchanger current (INCX), which together with If and decay of K(+) channels prompts the "M clock," the ensemble of sarcolemmal-electrogenic molecules, to generate APs. Prolongation of the average LCR period accompanies prolongation of the average AP beating interval (BI). Moreover, the prolongation of the average AP BI accompanies increased AP BI variability. We hypothesized that both the average AP BI and AP BI variability are dependent upon stochasticity of clock mechanisms reported by the variability of LCR period. We perturbed the coupled-clock system by directly inhibiting the M clock by ivabradine (IVA) or the Ca(2+) clock by cyclopiazonic acid (CPA). When either clock is perturbed by IVA (3, 10 and 30 μM), which has no direct effect on Ca(2+) cycling, or CPA (0.5 and 5 μM), which has no direct effect on the M clock ion channels, the clock system failed to achieve the basal AP BI and both AP BI and AP BI variability increased. The changes in average LCR period and its variability in response to perturbations of the coupled-clock system were correlated with changes in AP beating interval and AP beating interval variability. We conclude that the stochasticity within the coupled-clock system affects and is affected by the AP BI firing rate and rhythm via modulation of the effectiveness of clock coupling.
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA; Biomedical Engineering Faculty, Technion-IIT, Haifa, Israel. Electronic address: yaely@bm.technion.ac.il.
authors.forename: Yael
authors.initials: Y
authors.lastname: Yaniv
authors.affiliation: Translational Gerontology Branch, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Alexey E
authors.initials: AE
authors.lastname: Lyashkov
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Syevda
authors.initials: S
authors.lastname: Sirenko
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Toni-Rose
authors.initials: TR
authors.lastname: Guiriba
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Ziman
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA; Mathematics and Statistics Department, Loyola University, Baltimore, MD, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Morrell
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA. Electronic address: lakattae@grc.nia.nih.gov.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D000200:Action Potentials; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001683:Biological Clocks; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling; D007211:Indoles / Q000494:pharmacology; D000077550:Ivabradine; D009200:Myocardial Contraction; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D059010:Single-Cell Analysis; D012849:Sinoatrial Node / Q000166:cytology / Q000502:physiology*; D013269:Stochastic Processes
chemical_list: D001552:Benzazepines; D002121:Calcium Channel Blockers; D007211:Indoles; D000077550:Ivabradine; D002118:Calcium; C000543:cyclopiazonic acid
keywords: Ca(2+) cycling; Ion channels; Physiology; Sarcoplasmic reticulum; Sinoatrial nodal pacemaker cells