Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model
Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model
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DOI：
10.1152/ajpheart.01118.2008
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发表时间：
2009-03-01
影响因子：
4.8
通讯作者：
Lakatta, Edward G.
中科院分区：
文献类型：
--
作者：
Maltsev, Victor A.;Lakatta, Edward G.
Maltsev VA，Lakatta EG.在一个新的起搏细胞模型中，肌膜下钙离子时钟和肌膜电压时钟的协同作用赋予了强大而灵活的起搏功能。美国生理学杂志心脏循环生理学296：H594-H615，2009年。首次发表于2009年1月9日; doi：10.1152/ajpheart.01118.2008。近年来的实验研究表明，窦房结细胞（SANC）在舒张晚期除极（DD）过程中产生自发的、节律性的局部肌膜下钙释放（Ca 2 + clock），并通过激活Na+-Ca 2+交换电流（I-NCX）与经典的肌膜电压振荡器（membrane clock）相互作用。然而，现有的基本上膜界定的心脏起搏细胞的数值模型没有捕捉到时钟之间的这种和其他相互作用。使用大规模的膜时钟和钙离子循环的经典配方的参数分析，我们已经构建并初步探索了一个原型兔SANC模型具有两个时钟。我们的耦合振荡器系统具有更大的鲁棒性和灵活性比膜时钟单独工作。基于肌浆网（SR）的Ca 2+时钟的节律性自发Ca 2+释放通过晚DD I-NCX在更广泛的膜时钟参数范围内点燃节律性动作电位[e.例如，在一个实施例中，L型Ca 2+电流（I-CaL）和/或超极化激活（“有趣”）电流（I-f）电导]。系统Ca 2+时钟包括SR和肌膜Ca 2+通量，其优化细胞Ca 2+平衡以随着SR Ca 2+泵送速率增加而增加SR Ca 2+释放和晚期DD I-NCX的幅度，从而导致宽起搏频率调制（1.8-4.6 Hz）。相反，当Ca 2+时钟不变或缺乏时，通过膜时钟参数的速率调制范围基本上较小。当Ca 2+时钟被禁用时，用于故障安全SANC操作的系统参数空间显著缩小：没有节律性晚期DD I-NCX点火信号，膜时钟大幅减慢、变得节律失调或停止。总之，Ca 2+时钟是SANC功能的一个新的关键维度。的协同作用的耦合功能的Ca 2+和膜时钟赋予故障安全SANC操作在很大程度上变化的速率。
Maltsev VA, Lakatta EG. 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 296: H594-H615, 2009. First published January 9, 2009; doi:10.1152/ajpheart.01118.2008.-Recent experimental studies have demonstrated that sinoatrial node cells (SANC) generate spontaneous, rhythmic, local subsarcolemmal Ca2+ releases (Ca2+ clock), which occur during late diastolic depolarization (DD) and interact with the classic sarcolemmal voltage oscillator (membrane clock) by activating Na+-Ca2+ 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 Ca2+ 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 Ca2+ releases of sarcoplasmic reticulum (SR)-based Ca2+ clock ignite rhythmic action potentials via late DD I-NCX over much broader ranges of membrane clock parameters [e. g., L-type Ca2+ current (I-CaL) and/or hyperpolarization-activated ("funny") current (I-f) conductances]. The system Ca2+ clock includes SR and sarcolemmal Ca2+ fluxes, which optimize cell Ca2+ balance to increase amplitudes of both SR Ca2+ release and late DD I-NCX as SR Ca2+ 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 Ca2+ clock is unchanged or lacking. When Ca2+ 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 Ca2+ clock is a new critical dimension in SANC function. A synergism of the coupled function of Ca2+ and membrane clocks confers fail-safe SANC operation at greatly varying rates.