Superresolution modeling of calcium release in the heart.
Superresolution modeling of calcium release in the heart.
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DOI：
10.1016/j.bpj.2014.11.003
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发表时间：
2014-12-16
影响因子：
3.4
通讯作者：
Winslow, Raimond L.
中科院分区：
文献类型：
--
作者：
Walker, Mark A.;Williams, George S. B.;Kohl, Tobias;Lehnart, Stephan E.;Jafri, M. Saleet;Greenstein, Joseph L.;Lederer, W. J.;Winslow, Raimond L.
稳定的钙诱导的钙释放（CICR）是心脏兴奋-收缩偶联过程中维持细胞正常收缩的关键。心脏中CICR的基本元素是钙（Ca 2+）火花，它来自一组兰尼碱受体（RyR）。这些RyR簇的开放被触发以产生局部的、再生性的Ca 2+从肌浆网（SR）释放。SR的Ca 2+泄漏是细胞Ca 2+管理的重要过程，并且其受到火花保真度的关键影响，即，自发RyR开放触发Ca 2+火花的可能性。在这里，我们提出了一个详细的，三维模型的心脏Ca 2+释放单位，包括扩散，细胞内缓冲系统，和随机门控离子通道。该模型具有逼真的Ca 2+火花和强大的Ca 2+火花终止在广泛的几何形状和条件。此外，该模型捕捉到的细节的Ca 2+火花和非火花为基础的SR Ca 2+泄漏，它产生正常的兴奋-收缩耦合增益。我们表明，SR腔Ca 2+依赖性的RyR的调节是不是火花终止的关键，但它可以解释的SR Ca 2+泄漏负载关系在以前的实验工作中表现出的指数上升。在疾病的实验模型中观察到的子空间维度的扰动强烈改变了Ca 2+火花动力学。此外，我们发现，RyR团簇的结构也影响Ca 2+的释放特性，由于通过局部子空间Ca 2+浓度（[Ca 2 +]ss）的RyR间耦合的变化。这些结果说明RyR集群基于超分辨率受激发射耗尽显微镜。最后，我们提出了一种新的方法，通过该方法可以预测的火花保真度的RyR集群的结构信息的集群使用其邻接矩阵的最大特征值。这些结果提供了重要的见解CICR动力学在心脏，在正常和病理条件下。
Stable calcium-induced calcium release (CICR) is critical for maintaining normal cellular contraction during cardiac excitation-contraction coupling. The fundamental element of CICR in the heart is the calcium (Ca2+) spark, which arises from a cluster of ryanodine receptors (RyR). Opening of these RyR clusters is triggered to produce a local, regenerative release of Ca2+ from the sarcoplasmic reticulum (SR). The Ca2+ leak out of the SR is an important process for cellular Ca2+ management, and it is critically influenced by spark fidelity, i.e., the probability that a spontaneous RyR opening triggers a Ca2+ spark. Here, we present a detailed, three-dimensional model of a cardiac Ca2+ release unit that incorporates diffusion, intracellular buffering systems, and stochastically gated ion channels. The model exhibits realistic Ca2+ sparks and robust Ca2+ spark termination across a wide range of geometries and conditions. Furthermore, the model captures the details of Ca2+ spark and nonspark-based SR Ca2+ leak, and it produces normal excitation-contraction coupling gain. We show that SR luminal Ca2+-dependent regulation of the RyR is not critical for spark termination, but it can explain the exponential rise in the SR Ca2+ leak-load relationship demonstrated in previous experimental work. Perturbations to subspace dimensions, which have been observed in experimental models of disease, strongly alter Ca2+ spark dynamics. In addition, we find that the structure of RyR clusters also influences Ca2+ release properties due to variations in inter-RyR coupling via local subspace Ca2+ concentration ([Ca2+]ss). These results are illustrated for RyR clusters based on super-resolution stimulated emission depletion microscopy. Finally, we present a believed-novel approach by which the spark fidelity of a RyR cluster can be predicted from structural information of the cluster using the maximum eigenvalue of its adjacency matrix. These results provide critical insights into CICR dynamics in heart, under normal and pathological conditions.
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影响因子：
3.4
作者：
Franzini-Armstrong, C;Protasi, F;Ramesh, V
通讯作者：
Ramesh, V
影响因子：
37.8
作者：
Gómez, AM;Guatimosim, S;Lederer, WJ
通讯作者：
Lederer, WJ
影响因子：
3.8
作者：
Chen, Haiyan;Valle, Giorgia;Volpe, Pompeo
通讯作者：
Volpe, Pompeo
影响因子：
3.4
作者：
Greenstein, JL;Winslow, RL
通讯作者：
Winslow, RL
影响因子：
56.9
作者：
CHENG, H;LEDERER, WJ;CANNELL, MB
通讯作者：
CANNELL, MB