Life and death of a cardiac calcium spark.
Life and death of a cardiac calcium spark.
复制标题
心脏钙火花的生与死。
DOI：
10.1085/jgp.201311034
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Maltsev VA
中科院分区：
文献类型：
--
作者：
Stern MD;Ríos E;Maltsev VA
心肌细胞中的钙火花是肌浆网(SR)短暂的、局部的钙释放，被认为是由局部再生的钙诱导的钙释放(CICR)通过耦合的兰尼定受体(RYR)引起的。这种再生是如何终止的还不确定。我们对一个理想化的随机火花产生模型进行了数值模拟，假设只有两个状态(打开和关闭)的RyR门控方案。在放电过程中，SR内钙的局部耗竭是不可避免的，这可以通过中断CICR来终止火花，无论是否假设SR腔钙对RyR门控的调节。局部SR耗尽导致的火花终止并不牢固：在某些条件下，火花可以大大且可变地延长，通过随机磨损而终止--我们将这种现象称为“火花亚稳定”。火花荧光上升时间不能很好地反映钙释放的持续时间。利用一个高度简化的、确定性的耦合动力学模型，我们证明了火花亚稳态依赖于RyR门控和结SR再充注率的动力学关系。火花亚稳定的条件类似于已知的RyR2和CASQ2突变导致的危及生命的触发心律失常，通过改变RyR的动力学可以缓解火花亚稳定，其方式类似于已知的预防这些心律失常的药物的效果。该模型无法解释化学剥离的猫心房肌细胞中的火花幅度和上升时间的分布，这表明这种火花可能是更复杂的事件，涉及偶联的异质性或RyR亚群之间的局部传播。
Calcium sparks in cardiac myocytes are brief, localized calcium releases from the sarcoplasmic reticulum (SR) believed to be caused by locally regenerative calcium-induced calcium release (CICR) via couplons, clusters of ryanodine receptors (RyRs). How such regeneration is terminated is uncertain. We performed numerical simulations of an idealized stochastic model of spark production, assuming a RyR gating scheme with only two states (open and closed). Local depletion of calcium in the SR was inevitable during a spark, and this could terminate sparks by interrupting CICR, with or without assumed modulation of RyR gating by SR lumenal calcium. Spark termination by local SR depletion was not robust: under some conditions, sparks could be greatly and variably prolonged, terminating by stochastic attrition–a phenomenon we dub “spark metastability.” Spark fluorescence rise time was not a good surrogate for the duration of calcium release. Using a highly simplified, deterministic model of the dynamics of a couplon, we show that spark metastability depends on the kinetic relationship of RyR gating and junctional SR refilling rates. The conditions for spark metastability resemble those produced by known mutations of RyR2 and CASQ2 that cause life-threatening triggered arrhythmias, and spark metastability may be mitigated by altering the kinetics of the RyR in a manner similar to the effects of drugs known to prevent those arrhythmias. The model was unable to explain the distributions of spark amplitudes and rise times seen in chemically skinned cat atrial myocytes, suggesting that such sparks may be more complex events involving heterogeneity of couplons or local propagation among sub-clusters of RyRs.
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影响因子：
20.1
作者：
Cerrone, M;Colombi, B;Priori, SG
通讯作者：
Priori, SG
影响因子：
3.4
作者：
Hinch, R
通讯作者：
Hinch, R
影响因子：
--
作者：
BERS, DM;STIFFEL, VM
通讯作者：
STIFFEL, VM
影响因子：
5.5
作者：
Lukyanenko, V;Wiesner, TF;Györke, S
通讯作者：
Györke, S
影响因子：
3.4
作者：
Qin, Jia;Valle, Giorgia;Fill, Michael
通讯作者：
Fill, Michael