Calcium homeostasis in a local/global whole cell model of permeabilized ventricular myocytes with a Langevin description of stochastic calcium release
Calcium homeostasis in a local/global whole cell model of permeabilized ventricular myocytes with a Langevin description of stochastic calcium release
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透化心室肌细胞局部/整体全细胞模型中的钙稳态，具有随机钙释放的 Langevin 描述
DOI：
10.1152/ajpheart.00296.2014
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Smith, Gregory D.
中科院分区：
文献类型：
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作者：
Wang, Xiao;Weinberg, Seth H.;Hao, Yan;Sobie, Eric A.;Smith, Gregory D.
用群体密度方法模拟局部控制钙离子诱导的心肌细胞内钙离子释放，可以用来构建准确代表异质局部钙信号的最小全细胞模型。不幸的是，这种“局部/全局”全细胞模型的计算复杂性与钙释放单位(CAU)状态的数量成比例，这是每个CAU的兰尼定受体(RyRs)数量的快速增加的函数。在这里，我们提出了一种替代的方法，基于朗之万描述的与局部钙离子浓度([钙])相关的RyR的集体门控。这种方法的计算效率不再依赖于每个CAU的RYR数量。当RyR模型最小时，朗之万方程可以被一个单一的Fokker-Planck方程取代，从而产生一个极其紧凑和有效的局部/全局全细胞模型，该模型重现并帮助解释了最近研究通透性心室肌细胞内钙稳态的实验。我们的计算表明，肌浆[Ca~(2+)]升高通过肌浆网(SR)Ca~(2+)-ATPase介导的Ca~(2+)摄取促进肌浆网[Ca~(2+)]升高。然而，肌浆[Ca~(2+)]升高也可能激活RyRs，促进SR[Ca~(2+)]的随机释放，进而降低SR[Ca~(2+)]。增加肌浆[Ca~(2+)]会导致火花介导的释放呈指数增加，而非火花介导的释放呈线性增加，这与最近的实验一致。该模型显示了同一网络SR[Ca~(2+)]的两个稳态释放通量，这取决于肌浆[Ca~(2+)]的低或高。在后一种情况下，自发释放以保持强劲的钙火花的方式降低SR[钙]。
Population density approaches to modeling local control of Ca2+-induced Ca2+release in cardiac myocytes can be used to construct minimal whole cell models that accurately represent heterogeneous local Ca2+signals. Unfortunately, the computational complexity of such “local/global” whole cell models scales with the number of Ca2+release unit (CaRU) states, which is a rapidly increasing function of the number of ryanodine receptors (RyRs) per CaRU. Here we present an alternative approach based on a Langevin description of the collective gating of RyRs coupled by local Ca2+concentration ([Ca2+]). The computational efficiency of this approach no longer depends on the number of RyRs per CaRU. When the RyR model is minimal, Langevin equations may be replaced by a single Fokker-Planck equation, yielding an extremely compact and efficient local/global whole cell model that reproduces and helps interpret recent experiments that investigate Ca2+homeostasis in permeabilized ventricular myocytes. Our calculations show that elevated myoplasmic [Ca2+] promotes elevated network sarcoplasmic reticulum (SR) [Ca2+] via SR Ca2+-ATPase-mediated Ca2+uptake. However, elevated myoplasmic [Ca2+] may also activate RyRs and promote stochastic SR Ca2+release, which can in turn decrease SR [Ca2+]. Increasing myoplasmic [Ca2+] results in an exponential increase in spark-mediated release and a linear increase in nonspark-mediated release, consistent with recent experiments. The model exhibits two steady-state release fluxes for the same network SR [Ca2+] depending on whether myoplasmic [Ca2+] is low or high. In the later case, spontaneous release decreases SR [Ca2+] in a manner that maintains robust Ca2+sparks.