Subcellular calcium dynamics in a whole-cell model of an atrial myocyte
Subcellular calcium dynamics in a whole-cell model of an atrial myocyte
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DOI：
10.1073/pnas.1115855109
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发表时间：
2012-02-07
影响因子：
11.1
通讯作者：
Bootman, Martin D.
中科院分区：
文献类型：
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作者：
Thul, Ruediger;Coombes, Stephen;Bootman, Martin D.
在这项研究中，我们提出了一种创新的数学建模方法，可以详细描述心房肌细胞三维体积内的钙运动。该模型的基本方面是对钙释放位置和生理钙通量参数的几何逼真表示，再加上一个计算成本较低的框架。通过将非线性的Ca~(2+)兴奋性转化为阈值动力学，我们避免了常用于模拟Ca~(2+)转运的偏微分方程组的计算量大的时间步长。我们的方法成功地再现了用共聚焦成像观察到的心房肌细胞钙信号的关键特征。特别是，该模型显示了在兴奋-收缩耦合过程中发生在心房肌细胞内的向心性钙波，以及正性变力刺激对钙信号空间分布的影响。除了模型的这一验证，我们的模拟还揭示了关于钙离子在心房肌细胞内扩散的意外观察。特别是，该模型描述了钙离子在心房肌细胞特定z盘内的ryanodine受体簇之间的移动。此外，我们证明改变钙离子释放的强度、兰尼定受体的不稳定程度、起始刺激的大小或引入随机的钙离子通道活动都可以引起心律失常的行波的成核。该模型提供了对亚细胞钙信号的启动和传播的临床相关见解，这些信号目前超出了成像技术的范围。
In this study, we present an innovative mathematical modeling approach that allows detailed characterization of Ca2+ movement within the three-dimensional volume of an atrial myocyte. Essential aspects of the model are the geometrically realistic representation of Ca2+ release sites and physiological Ca2+ flux parameters, coupled with a computationally inexpensive framework. By translating nonlinear Ca2+ excitability into threshold dynamics, we avoid the computationally demanding time stepping of the partial differential equations that are often used to model Ca2+ transport. Our approach successfully reproduces key features of atrial myocyte Ca2+ signaling observed using confocal imaging. In particular, the model displays the centripetal Ca2+ waves that occur within atrial myocytes during excitation-contraction coupling, and the effect of positive inotropic stimulation on the spatial profile of the Ca2+ signals. Beyond this validation of the model, our simulation reveals unexpected observations about the spread of Ca2+ within an atrial myocyte. In particular, the model describes the movement of Ca2+ between ryanodine receptor clusters within a specific z disk of an atrial myocyte. Furthermore, we demonstrate that altering the strength of Ca2+ release, ryanodine receptor refractoriness, the magnitude of initiating stimulus, or the introduction of stochastic Ca2+ channel activity can cause the nucleation of proarrhythmic traveling Ca2+ waves. The model provides clinically relevant insights into the initiation and propagation of subcellular Ca2+ signals that are currently beyond the scope of imaging technology.