Stochastic Simulation Of Excitation-contraction Coupling

工作总结2D现象学模型已被广泛运用，以产生统计数据，显示钙时钟的周期性如何随着RyR钙释放电流的增加而出现，从而使时钟与膜电流一起调节心率。 这些模拟结果已发表在《生物物理学杂志》上。完整的蒙特-卡罗耦合模型与一个单一的细胞溶质室已更新，包括在个别钙释放终端的交界SR的钙的局部消耗的影响。模拟的并行模型上运行Biowulf证实，局部消耗钙火花终止的关键贡献，它足以作为唯一的终止机制。 然而，在这种情况下，SR钙的腔内扩散速率和RyR的门控动力学之间存在关键关系，必须满足该关系以防止火花延迟终止的不稳定性。 在钙超载的情况下，单细胞溶胶耦合模型不振荡。 这清楚地表明，有必要使用3D耦合模型来模拟负责钙时钟作用的传播局部释放。 一种新的3D算法，结合了全耦合模型与空间分辨胞质空间使用运营商分裂方法是在最后阶段的发展，并将用于研究钙释放夹带与膜电流在一个现实的生物物理模型的方式。

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.