The ryanodine receptor patchwork: knitting calcium spark dynamics.
The ryanodine receptor patchwork: knitting calcium spark dynamics.
复制标题
兰尼碱受体拼凑而成：编织钙火花动力学。
DOI：
10.1016/j.bpj.2014.10.068
复制
发表时间：
2014
影响因子：
3.4
通讯作者：
Sobie,EricA
中科院分区：
文献类型：
--
作者：
Núñez-Acosta,Elisa;Sobie,EricA
Ca 2+火花是微观（1-2 mm）的概率事件，反映了肌浆网（SR）膜中释放通道簇（称为ryanodine受体（RyR））释放Ca 2+。虽然火花已经在骨骼肌和平滑肌中观察到，但它们在心脏细胞中的研究最为深入。每个心脏Ca 2+火花反映了包含相对少量（10-100）RyR的簇的随机门控，并且典型的心室肌细胞可以包含10，000 - 20，000个这样的RyR簇，也称为Ca 2+释放单位（CRU）。在火花首次被发现后的21年里，这些事件受到了研究界的极大关注。Ca 2+火花的部分吸引力在于它们是分子和细胞尺度之间的联系。火花的测量允许人们对个体RyR的门控进行推断，并且，反过来，火花行为决定了细胞水平事件的特征，例如静止肌细胞中SR的Ca 2+泄漏和由膜去极化触发的Ca 2+瞬变。火花也是再生的、传播的Ca 2+波的基本基础，其可以潜在地引发心律失常，因此这些事件在细胞内Ca 2+处理和病理性电信号之间形成桥梁。由于涉及在多个空间尺度上理解SR Ca 2+释放的复杂性，数学建模经常被用作开发定量预测的工具。心脏Ca 2+火花的模拟是一个历史相对悠久的研究领域，已经产生了一些值得注意的例子，其中数学建模产生了领先于现有实验记录状态的概念性进步，这使得模拟能够激发后续的实验工作。在最著名的例子中，Stern（2）在1992年发展了“局部控制”理论，其基础是简单的确定性数学模型不能重现实验观测。这基本上是对基本事件存在的一个预测，这一假设在第二年首次报道了Ca 2+火花的记录时得到了证实（1）。同样，在2002年，Sobie et al. (3)发表了心脏Ca 2+火花的随机数学模型，并提出SR [Ca 2 +]的强烈局部耗竭对于确保这些事件的可靠终止是必不可少的。随后的实验证实了局部消耗的发生，并提供了令人信服的证据，它确实是至关重要的火花终止。在这种情况下和上面提到的局部控制理论中，建模预测都很有价值，部分原因是它们为解释后来的实验数据建立了概念框架。这使得研究人员能够将数据解释为与模型预测一致或不一致，从而达成共识，而不是无休止地争论令人困惑的实验结果。在本期的《生物物理学杂志》上，步行者等。(4)提出了一个心脏Ca 2+火花模型，可能具有类似的长期影响。如下所述，文章产生了关于CRU的分子水平结构如何影响Ca 2+火花特性的有趣预测，并且结果肯定被证明对解释获得的新数据有用。火花建模历史的另一个方面有助于将步行者等人的结果置于上下文中。微观心脏Ca 2+信号传导的模拟通常沿着两个不同轨道之沿着进行（5）。在一类中，许多研究使用蒙特卡罗方法来...
Ca2+ sparks are microscopic (1–2 mm), probabilistic events that reflect release of Ca2+ from clusters of release channels, known as ryanodine receptors (RyRs), in the sarcoplasmic reticulum (SR) membrane. Although sparks have been observed in skeletal and smooth muscle, they have been most intensively studied in heart cells. Each cardiac Ca2+ spark reflects the stochastic gating of a cluster containing a relatively small number (10–100) of RyRs, and a typical ventricular myocyte may contain 10,000–20,000 of such RyR clusters, also known as Ca2+ release units (CRUs). In the 21 years since sparks were first discovered (1), these events have received considerable attention from the research community. Part of the appeal of Ca2+ sparks is the fact that they are a link between the molecular and cellular scales. Measurements of sparks allow one to make inferences about the gating of individual RyRs, and, in turn, spark behavior determines the characteristics of cellular-level events such as Ca2+ leak from the SR in quiescent myocytes and Ca2+ transients triggered by membrane depolarization. Sparks are also the fundamental basis of regenerative, propagating Ca2+ waves that can potentially initiate arrhythmias, so these events form a bridge between intracellular Ca2+ handling and pathological electrical signaling. Because of the complexity involved in understanding SR Ca2+ release across multiple spatial scales, mathematical modeling has frequently been employed as a tool for developing quantitative predictions. Simulation of cardiac Ca2+ sparks, a research area with a relatively long history, has produced some notable examples in which mathematical modeling produced a conceptual advance that was ahead of the existing state of experimental recordings, and this allowed the simulations to inspire subsequent experimental work. In the most celebrated case, Stern (2) developed the ‘‘local control’’theory in 1992 on the basis of the observation that simple deterministic mathematical models could not reproduce experimental observations. This was essentially a prediction for the existence of elementary events, a hypothesis that was confirmed the following year when recordings of Ca2+ sparks were first reported (1). Similarly, in 2002, Sobie et al.(3) published a stochastic mathematical model of the cardiac Ca2+ spark and proposed that strong local depletion of SR [Ca2+] was essential to ensure the reliable termination of these events. Subsequent experiments confirmed that local depletion occurs and provided compelling evidence that it is indeed critical for spark termination. In both this case and the local control theory mentioned above, the modeling predictions were valuable in part because they established a conceptual framework for the interpretation of later experimental data. This allowed investigators to interpret data as either consistent with or inconsistent with modeling predictions, thereby achieving consensus, rather than arguing endlessly about confusing experimental results. In this issue of the Biophysical Journal, Walker et al.(4) present a cardiac Ca2+ spark model that may potentially have a similar long-term impact. As described below, the article generates interesting predictions about how the molecular-level structure of the CRU influences Ca2+ spark properties, and the results are certain to prove useful for interpreting new data as they are obtained.An additional aspect of spark modeling history helps to place the results of Walker et al. in context. Simulations of microscopic cardiac Ca2+ signaling have generally proceeded along one of two different tracks (5). In one category, many studies have used Monte Carlo methods to …