Stochastic Simulation Of Excitation-contraction Coupling

工作概述2D现象学模型已被广泛应用来生成统计数据，显示随着RyR钙释放电流的增加，钙时钟的周期性如何出现，从而允许时钟与膜电流缠绕以调节心率。这些模拟的结果已经发表在生物物理杂志上。完整的蒙特卡罗耦合模型中的单个胞浆隔室已经被更新，以包括在连接SR的单个钙释放末端的局部钙耗竭的影响。在Biowulf上运行的并行化模型的模拟证实了局部耗尽对钙火花终止的关键贡献，并且它足以作为唯一的终止机制。然而，在这种情况下，SR钙在腔内的扩散速度和RyR的门控动力学之间存在着关键的关系，必须满足这一点才能防止延迟终止的火花不稳定。在钙超载的情况下，单细胞溶质偶联模型不发生钙化。这清楚地表明，有必要使用3D耦合模型来模拟负责钙钟作用的传播的局部释放。一种新的3D算法，使用算子分裂方法将完整的耦合模型与空间分辨的胞浆空间结合在一起，处于开发的最后阶段，将用于研究现实生物物理模型中钙释放与膜电流夹带的方式。

SUMMARY OF WORK The 2D phenomenalogical model has been exercised extensively to generate statistics showing how periodicity of the calcium clock emerges as the RyR calcium release current is increased, allowing the clock to entrain with membrane currents to regulate the heart rate. The results of those simulations have been published in Biophysical Journal. The full Monte-Carlo couplon model with a single cytosolic compartment has been updated to include the effects of local depletion of calcium at individual calcium release terminals of the junctional SR. Simulations of the parallelized model run on Biowulf confirm that local depletion makes a critical contribution to calcium spark termination and that it suffices as the only termination mechanism. However, in that case, there is a critical relationship between the intra-lumenal diffusion rate of SR calcium and the gating kinetics of the RyR that must be satisfied to prevent instability of sparks with delayed termination. Under calcium overload, the single-cytosol couplon model does not osciallate. This makes it clear that it will be necessary to use a 3D couplon model to simulate the propagated local releases responsible for calcium clock action. A new 3D algorithm, combining the full couplon model with a spatially resolved cytosolic space using an operator splitting method is in the final stages of development and will be used to study the way in which calcium releases entrain with membrane currents in a realistic biophysical model.