Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells

Yael Yaniv, Alexey E. Lyashkov, Syevda Sirenko, Yosuke Okamoto, Toni Rose Guiriba, Bruce D. Ziman, Christopher H. Morrell, Edward Lakatta

Research output: Contribution to journalArticle

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 "Ca2+ clock" within the sarcoplasmic reticulum, spontaneously activate during diastole and discharge local Ca2+ releases (LCRs) beneath the cell surface membrane; clock crosstalk occurs as LCRs activate an inward Na+/Ca2+ 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 Ca2+ clock by cyclopiazonic acid (CPA). When either clock is perturbed by IVA (3, 10 and 30μM), which has no direct effect on Ca2+ cycling, or CPA (0.5 and 5μM), 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.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume77
DOIs
StatePublished - Dec 1 2014
Externally publishedYes

Fingerprint

Sinoatrial Node
Action Potentials
ivabradine
Ryanodine Receptor Calcium Release Channel
Diastole
Sarcoplasmic Reticulum
Ion Channels
Cell Membrane

Keywords

  • Ca cycling
  • Ion channels
  • Physiology
  • Sarcoplasmic reticulum
  • Sinoatrial nodal pacemaker cells

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells. / Yaniv, Yael; Lyashkov, Alexey E.; Sirenko, Syevda; Okamoto, Yosuke; Guiriba, Toni Rose; Ziman, Bruce D.; Morrell, Christopher H.; Lakatta, Edward.

In: Journal of Molecular and Cellular Cardiology, Vol. 77, 01.12.2014, p. 1-10.

Research output: Contribution to journalArticle

Yaniv, Yael ; Lyashkov, Alexey E. ; Sirenko, Syevda ; Okamoto, Yosuke ; Guiriba, Toni Rose ; Ziman, Bruce D. ; Morrell, Christopher H. ; Lakatta, Edward. / Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells. In: Journal of Molecular and Cellular Cardiology. 2014 ; Vol. 77. pp. 1-10.
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AU - Yaniv, Yael

AU - Lyashkov, Alexey E.

AU - Sirenko, Syevda

AU - Okamoto, Yosuke

AU - Guiriba, Toni Rose

AU - Ziman, Bruce D.

AU - Morrell, Christopher H.

AU - Lakatta, Edward

PY - 2014/12/1

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AB - 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 "Ca2+ clock" within the sarcoplasmic reticulum, spontaneously activate during diastole and discharge local Ca2+ releases (LCRs) beneath the cell surface membrane; clock crosstalk occurs as LCRs activate an inward Na+/Ca2+ 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 Ca2+ clock by cyclopiazonic acid (CPA). When either clock is perturbed by IVA (3, 10 and 30μM), which has no direct effect on Ca2+ cycling, or CPA (0.5 and 5μM), 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.

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