Termination of cardiac Ca2+ sparks:: An investigative mathematical model of calcium-induced calcium release
Termination of cardiac Ca2+ sparks:: An investigative mathematical model of calcium-induced calcium release
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DOI：
10.1016/s0006-3495(02)75149-7
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发表时间：
2002-07-01
影响因子：
3.4
通讯作者：
Jafri, MS
中科院分区：
文献类型：
--
作者：
Sobie, EA;Dilly, KW;Jafri, MS
当一组肌浆网(SR)通道(Ryanodine受体或RyRs)打开以局部再生的方式释放钙时，就会产生钙火花。钙火花通常是由钙离子通过邻近肌簇的肌膜或横管膜内流触发的，已被证明是心肌兴奋收缩偶联的基本信号事件。然而，钙离子火花如何终止的问题仍然是一个核心的悬而未决的问题。在这里，我们提出了一个新的模型，“粘性簇”，SR钙离子释放，模拟钙离子火花行为，并实现强大的钙离子火花终止。在这个原本很简单的模型中，RyR行为的两个新的记录特征被纳入其中：“耦合门控”和依赖于SR腔内[Ca~(2+)]的开放速率。用蒙特卡罗方法模拟了10-100 RyR团簇中局部钙离子诱导的钙离子释放。释放被触发后，来自RyRs的钙离子流量扩散到胞浆中，并与细胞内缓冲液和荧光钙指示剂Fluo-3结合，产生模型钙火花。粘性星系团模型产生的C2+火花与实验观察到的相似，而Ca~(2+)火花的持续时间和幅度对团簇中RyR的数量几乎不敏感。正如心脏细胞研究所预期的那样，模型中的自发钙闪光率随着胞浆或肌浆网[Ca+]的升高而增加。此外，RyR偶联的减少会导致模型钙离子火花的延长，就像FK506处理会延长心肌细胞的钙离子火花一样。这一新的钙离子火花行为模型提供了对钙离子火花终止新假说的“原则性证明”检验，并再现了实验观察到的钙离子火花的关键特征。
A Ca2+ spark arises when a cluster of sarcoplasmic reticulum (SR) channels (ryanodine receptors or RyRs) opens to release calcium in a locally regenerative manner. Normally triggered by Ca2+ influx across the sarcolemmal or transverse tubule membrane neighboring the cluster, the Ca2+ spark has been shown to be the elementary Ca2+ signaling event of excitation-contraction coupling in heart muscle. However, the question of how the Ca2+ spark terminates remains a central, unresolved issue. Here we present a new model, "sticky cluster," of SR Ca2+ release that simulates Ca2+ spark behavior and enables robust Ca2+ spark termination. Two newly documented features of RyR behavior have been incorporated in this otherwise simple model: "coupled gating" and an opening rate that depends on SR lumenal [Ca2+]. Using a Monte Carlo method, local Ca2+-induced Ca2+ release from clusters containing between 10 and 100 RyRs is modeled. After release is triggered, Ca2+ flux from RyRs diffuses into the cytosol and binds to intracellular buffers and the fluorescent Ca2+ indicator fluo-3 to produce the model Ca2+ spark. C2+ sparks generated by the sticky cluster model resemble those observed experimentally, and Ca2+ spark duration and amplitude are largely insensitive to the number of RyRs in a cluster. As expected from heart cell investigation, the spontaneous Ca2+ spark rate in the model increases with elevated cytosolic or SR lumenal [Ca2+]. Furthermore, reduction of RyR coupling leads to prolonged model Ca2+ sparks just as treatment with FK506 lengthens Ca2+ sparks in heart cells. This new model of Ca2+ spark behavior provides a "proof of principle" test of a new hypothesis for Ca2+ spark termination and reproduces critical features of Ca2+ sparks observed experimentally.