Numerical Analysis of Ca2+ Signaling in Rat Ventricular Myocytes with Realistic Transverse-Axial Tubular Geometry and Inhibited Sarcoplasmic Reticulum
Numerical Analysis of Ca2+ Signaling in Rat Ventricular Myocytes with Realistic Transverse-Axial Tubular Geometry and Inhibited Sarcoplasmic Reticulum
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DOI：
10.1371/journal.pcbi.1000972
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发表时间：
2010-10-01
影响因子：
4.3
通讯作者：
Michailova, Anushka P.
中科院分区：
文献类型：
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作者：
Cheng, Yuhui;Yu, Zeyun;Michailova, Anushka P.
哺乳动物心室肌细胞的T管是细胞膜的内陷，出现在每条Z线上。这些内陷在细胞内分支，形成一个复杂的网络，允许电信号的快速传播，从而同步升高细胞内钙(Ca~(2+))。为了研究T管的显微解剖结构和膜钙通量的分布对心肌兴奋收缩偶联的影响，我们建立了大鼠心室肌细胞钙信号、缓冲和扩散的三维连续统模型。横轴T管的几何形状是由光学显微镜结构数据得出的。为了求解非线性反应扩散方程组，我们扩展了SMOL软件工具(http://mccammon.ucsd.edu/smol/).分析表明，对钙信号的定量理解需要更准确地了解t-小管的超微结构和沿肌膜的钙通量分布。结果揭示了流动和固定的钙离子缓冲液的重要作用，包括钙离子指示剂染料。与实验一致的是，在荧光染料和抑制肌浆网存在的情况下，当钙流量沿肌膜均匀分布时，去极化引起的钙瞬变没有可检测到的差异。在没有荧光染料的情况下，预测了强烈的不均匀的钙信号。即使在钙离子内流时达到的钙离子轻度升高，在狭窄的肌膜下间隙也可以发现大而陡峭的钙离子梯度。该模型预测，分支T管结构和沿细胞膜的正常钙通量密度的变化支持大鼠心肌细胞钙波的启动和传播。
The t-tubules of mammalian ventricular myocytes are invaginations of the cell membrane that occur at each Z-line. These invaginations branch within the cell to form a complex network that allows rapid propagation of the electrical signal, and hence synchronous rise of intracellular calcium (Ca2+). To investigate how the t-tubule microanatomy and the distribution of membrane Ca2+ flux affect cardiac excitation-contraction coupling we developed a 3-D continuum model of Ca2+ signaling, buffering and diffusion in rat ventricular myocytes. The transverse-axial t-tubule geometry was derived from light microscopy structural data. To solve the nonlinear reaction-diffusion system we extended SMOL software tool (http://mccammon.ucsd.edu/smol/). The analysis suggests that the quantitative understanding of the Ca2+ signaling requires more accurate knowledge of the t-tubule ultra-structure and Ca2+ flux distribution along the sarcolemma. The results reveal the important role for mobile and stationary Ca2+ buffers, including the Ca2+ indicator dye. In agreement with experiment, in the presence of fluorescence dye and inhibited sarcoplasmic reticulum, the lack of detectible differences in the depolarization-evoked Ca2+ transients was found when the Ca2+ flux was heterogeneously distributed along the sarcolemma. In the absence of fluorescence dye, strongly non-uniform Ca2+ signals are predicted. Even at modest elevation of Ca2+, reached during Ca2+ influx, large and steep Ca2+ gradients are found in the narrow sub-sarcolemmal space. The model predicts that the branched t-tubule structure and changes in the normal Ca2+ flux density along the cell membrane support initiation and propagation of Ca2+ waves in rat myocytes.