Yaniv Yael, Lyashkov Alexey E, Sirenko Syevda, Okamoto Yosuke, Guiriba Toni-Rose, Ziman Bruce D, Morrell Christopher H, Lakatta Edward G
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.
Translational Gerontology Branch, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
J Mol Cell Cardiol. 2014 Dec;77:1-10. doi: 10.1016/j.yjmcc.2014.09.008. Epub 2014 Sep 22.
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.
最近的证据表明，孤立的窦房结细胞（SANC）的自发动作电位（AP）受两个时钟所体现的随机机制系统调节：肌浆网内“Ca(2+)时钟”的ryanodine受体，在舒张期自发激活并释放细胞表面膜下方的局部Ca(2+)释放（LCR）；当LCR激活内向Na(+)/Ca(2+)交换电流（INCX）时发生时钟串扰，INCX与If以及K(+)通道的衰减一起促使“M时钟”（肌膜电生分子的集合）产生AP。平均LCR周期的延长伴随着平均AP搏动间隔（BI）的延长。此外，平均AP BI的延长伴随着AP BI变异性的增加。我们假设平均AP BI和AP BI变异性均取决于由LCR周期变异性报告的时钟机制的随机性。我们通过用伊伐布雷定（IVA）直接抑制M时钟或用环匹阿尼酸（CPA）抑制Ca(2+)时钟来干扰耦合时钟系统。当用对Ca(2+)循环无直接影响的IVA（3、10和30μM）或对M时钟离子通道无直接影响的CPA（0.5和5μM）干扰任何一个时钟时，时钟系统无法达到基础AP BI，并且AP BI和AP BI变异性均增加。耦合时钟系统受扰动时平均LCR周期及其变异性的变化与AP搏动间隔和AP搏动间隔变异性的变化相关。我们得出结论，耦合时钟系统内的随机性通过调节时钟耦合的有效性来影响AP BI发放率和节律，并受其影响。
