Modeling effects of L-type ca(2+) current and na(+)-ca(2+) exchanger on ca(2+) trigger flux in rabbit myocytes with realistic T-tubule geometries.
Modeling effects of L-type ca(2+) current and na(+)-ca(2+) exchanger on ca(2+) trigger flux in rabbit myocytes with realistic T-tubule geometries.
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DOI：
10.3389/fphys.2012.00351
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发表时间：
2012
影响因子：
4
通讯作者：
Michailova AP
中科院分区：
文献类型：
--
作者：
Kekenes-Huskey PM;Cheng Y;Hake JE;Sachse FB;Bridge JH;Holst MJ;McCammon JA;McCulloch AD;Michailova AP
兔心室肌细胞的横管系统由细胞膜内陷（t小管）组成，这是有效的心脏兴奋-收缩耦合所必需的。在这项研究中，我们研究了t小管微观解剖、l型Ca2+通道（LCC）聚类和l型Ca2+电流对Na+/Ca2+交换器的变构激活如何影响细胞内Ca2+动力学。我们的模型包括兔心室肌细胞单个t小管及其周围半肌节的真实三维几何形状。空间分布的膜离子转运体（LCC、Na+/Ca2+交换器、肌层Ca2+泵和肌层Ca2+泄漏）和固定和移动Ca2+缓冲液（肌钙蛋白C、ATP、钙调蛋白和Fluo-3）的影响也被考虑在内。我们使用了一个耦合的反应-扩散系统来描述自由和缓冲细胞内Ca2+的时空浓度分布。我们从l型Ca2+电流的电压箝位协议和兔细胞中Ca2+浓度谱的线扫描记录中获得参数，其中肌浆网被禁用。我们的模型结果与加载50 μM Fluo-3的肌细胞中全局Ca2+瞬态的实验测量结果一致。我们发现细胞质和肌膜内的局部Ca2+浓度，以及Ca2+穿过细胞膜的局部触发通量，对t小管微观结构和膜Ca2+通量分布的细节很敏感。该模型还预测，局部Ca2+触发通量至少比全细胞Ca2+触发通量高三到八倍。我们还发现，Na+/Ca2+交换器上的变构Ca2+结合位点的激活可以提供一种调节体内全局和局部Ca2+触发通量的机制。我们的研究表明，改进的结构和功能模型可以提高我们对l型和Na+/Ca2+交换通量对细胞内Ca2+动力学的贡献的理解。
The transverse tubular system of rabbit ventricular myocytes consists of cell membrane invaginations (t-tubules) that are essential for efficient cardiac excitation-contraction coupling. In this study, we investigate how t-tubule micro-anatomy, L-type Ca2+ channel (LCC) clustering, and allosteric activation of Na+/Ca2+ exchanger by L-type Ca2+ current affects intracellular Ca2+ dynamics. Our model includes a realistic 3D geometry of a single t-tubule and its surrounding half-sarcomeres for rabbit ventricular myocytes. The effects of spatially distributed membrane ion-transporters (LCC, Na+/Ca2+ exchanger, sarcolemmal Ca2+ pump, and sarcolemmal Ca2+ leak), and stationary and mobile Ca2+ buffers (troponin C, ATP, calmodulin, and Fluo-3) are also considered. We used a coupled reaction-diffusion system to describe the spatio-temporal concentration profiles of free and buffered intracellular Ca2+. We obtained parameters from voltage-clamp protocols of L-type Ca2+ current and line-scan recordings of Ca2+ concentration profiles in rabbit cells, in which the sarcoplasmic reticulum is disabled. Our model results agree with experimental measurements of global Ca2+ transient in myocytes loaded with 50 μM Fluo-3. We found that local Ca2+ concentrations within the cytosol and sub-sarcolemma, as well as the local trigger fluxes of Ca2+ crossing the cell membrane, are sensitive to details of t-tubule micro-structure and membrane Ca2+ flux distribution. The model additionally predicts that local Ca2+ trigger fluxes are at least threefold to eightfold higher than the whole-cell Ca2+ trigger flux. We found also that the activation of allosteric Ca2+-binding sites on the Na+/Ca2+ exchanger could provide a mechanism for regulating global and local Ca2+ trigger fluxes in vivo. Our studies indicate that improved structural and functional models could improve our understanding of the contributions of L-type and Na+/Ca2+ exchanger fluxes to intracellular Ca2+ dynamics.
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影响因子：
3.7
作者：
Crossman DJ;Ruygrok PN;Soeller C;Cannell MB
通讯作者：
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