Stabilization of diastolic calcium signal via calcium pump regulation of complex local calcium releases and transient decay in a computational model of cardiac pacemaker cell with individual release channels.
Stabilization of diastolic calcium signal via calcium pump regulation of complex local calcium releases and transient decay in a computational model of cardiac pacemaker cell with individual release channels.
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DOI：
10.1371/journal.pcbi.1005675
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发表时间：
2017-08
影响因子：
4.3
通讯作者：
Stern MD
中科院分区：
文献类型：
--
作者：
Maltsev AV;Maltsev VA;Stern MD
肌浆网（SR）的细胞内局部钙释放（LCR）通过激活心脏起搏过程中的生电Na/Ca交换器（NCX）来调节心脏起搏细胞的功能。先前的研究表明，通过钙泵，释放和NCX的复杂的局部串扰的LCR调节的强大的补偿机制的存在。研究这些机制的一个主要障碍是LCR表现出复杂的Ca释放传播模式（包括合并和分离），尚未被表征。在这里，我们开发了新的术语，分类和计算机算法的自动检测数值模拟LCR和检查LCR监管SR钙泵送率（PUP），提供了一个重要的贡献战斗或飞行的反应。在我们的模拟中，更快的SR钙泵加速动作电位诱导的钙瞬变衰减，并迅速清除细胞膜下的钙在胆固醇，防止过早释放。然后SR产生更早、更同步和更强的舒张期LCR信号，激活更早和更大的内向NCX电流。在较高Pup下的LCR表现出更大的振幅和更快的传播，彼此碰撞更多。LCR与Ca瞬时衰减重叠，导致平均舒张[Ca]最低点升高至约200 nM（Pup = 24 mM/s）。背景Ca（在缺乏LCR的位置）在高Pup时快速衰减至静息Ca水平（<100 nM），但在低Pup时在较慢衰减期间保持升高。在较高Pup下，通过较大LCR振幅促进释放传播，而在低Pup下，通过较高背景Ca促进释放传播。虽然在低Pup LCR显示较小的振幅，其较大的持续时间和大小与较长的瞬态衰减相结合，稳定了舒张期Ca和NCX电流信号的积分。因此，SR Ca泵和释放通道的局部相互作用调节LCR和Ca瞬态衰减，以确保在宽速率范围内的故障安全起搏器单元操作。生命的重要节律，即心跳，是由专门的心脏起搏细胞保证的。基于Hodgkin-Huxley膜激发理论及其对心脏细胞的应用，心脏起搏时钟长期以来被认为本质上是由时间和电压依赖性离子通道的集合驱动的表面膜振荡器，即膜时钟。然而，最近的研究发现，细胞膜时钟与细胞内钙振荡器（称为钙时钟）紧密结合。钙时钟产生节律性的、舒张期局部传播的钙从肌浆网释放，肌浆网是细胞主要的钙储存，其通过钙泵被钙重新填充。释放的Ca激活Na/Ca交换器，产生内向电流并加速舒张期去极化。尽管它们很重要，但当地的释放量尚未得到系统的研究。在这里，我们开发了一种新的计算机算法，自动检测，分类和分析的局部钙释放产生的一个最近的计算模型的窦房结细胞。然后，我们研究了如何释放的钙泵，钙时钟的主要功能组件的调节。我们发现了违反直觉的行为，稳定舒张期钙信号质量，并确保故障安全起搏器在不同的泵送率操作。
Intracellular Local Ca releases (LCRs) from sarcoplasmic reticulum (SR) regulate cardiac pacemaker cell function by activation of electrogenic Na/Ca exchanger (NCX) during diastole. Prior studies demonstrated the existence of powerful compensatory mechanisms of LCR regulation via a complex local cross-talk of Ca pump, release and NCX. One major obstacle to study these mechanisms is that LCR exhibit complex Ca release propagation patterns (including merges and separations) that have not been characterized. Here we developed new terminology, classification, and computer algorithms for automatic detection of numerically simulated LCRs and examined LCR regulation by SR Ca pumping rate (Pup) that provides a major contribution to fight-or-flight response. In our simulations the faster SR Ca pumping accelerates action potential-induced Ca transient decay and quickly clears Ca under the cell membrane in diastole, preventing premature releases. Then the SR generates an earlier, more synchronized, and stronger diastolic LCR signal activating an earlier and larger inward NCX current. LCRs at higher Pup exhibit larger amplitudes and faster propagation with more collisions to each other. The LCRs overlap with Ca transient decay, causing an elevation of the average diastolic [Ca] nadir to ~200 nM (at Pup = 24 mM/s). Background Ca (in locations lacking LCRs) quickly decays to resting Ca levels (<100 nM) at high Pup, but remained elevated during slower decay at low Pup. Release propagation is facilitated at higher Pup by a larger LCR amplitude, whereas at low Pup by higher background Ca. While at low Pup LCRs show smaller amplitudes, their larger durations and sizes combined with longer transient decay stabilize integrals of diastolic Ca and NCX current signals. Thus, the local interplay of SR Ca pump and release channels regulates LCRs and Ca transient decay to insure fail-safe pacemaker cell operation within a wide range of rates. Life’s vital rhythm, the heartbeat is guaranteed by specialized, cardiac pacemaker cells. Based upon the Hodgkin-Huxley membrane excitation theory and its application to cardiac cells, the cardiac pacemaker clock has been, for a long time, to be considered essentially a surface membrane oscillator, i.e. a membrane clock, driven by an ensemble of time- and voltage-dependent ion channels. More recent studies, however, discovered a tight integration of the membrane clock with an intracellular Ca oscillator (dubbed Ca clock). The Ca clock generates rhythmic, diastolic locally propagating Ca releases from sarcoplasmic reticulum, a cell major Ca store, that is refilled with Ca via a Ca pump. The released Ca activates Na/Ca exchanger that generates an inward current and accelerates the diastolic depolarization. Despite their importance, the local releases have not been systematically studied. Here we developed a new computer algorithm for automatic detection, classification, and analysis of local Ca releases generated by a recent computational model of a sinoatrial node cell. Then we investigated how the releases are regulated by the Ca pump, a major functional component of Ca clock. We discovered counterintuitive behaviors stabilizing diastolic Ca signal mass and ensuring fail-safe pacemaker operation at various pumping rates.
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影响因子：
20.1
作者：
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