Stochastic Simulation Of Excitation-contraction Coupling

二维现象学模型已被广泛应用，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，允许时钟随膜电流携带以调节心率。这些模拟的结果已经发表在《生物物理杂志》上。具有单个细胞质室的完整蒙特卡罗耦合模型已被更新，以包括在连接层的单个钙释放末端钙的局部耗尽的影响。在Biowulf上运行的并行模型的模拟证实，局部耗尽对钙火花终止起关键作用，并且它足以作为唯一的终止机制。然而，在这种情况下，SR钙的腔内扩散速率与RyR的门控动力学之间必须满足临界关系，以防止延迟终止的火花不稳定。在钙超载的情况下，单细胞质偶联子模型不振荡。这清楚地表明，有必要使用三维耦合子模型来模拟负责钙时钟作用的传播局部释放。新的3D算法将全耦合子模型与使用算子分裂方法进行空间分辨的细胞质空间相结合，现已完成，并演示了局部钙释放（lcr）在模拟窦房结细胞中的局部和全局传播。现在，该模型明确地包括了与一整套表面膜电流的耦合，并证明了lcr可以驱动这些起搏器细胞的自发动作电位节律的Lakatta-Maltsev机制。初步结果表明，这一机制，连同假定的局部SR钙耗尽终止释放的作用，对这些细胞中ryanodine受体的放置和聚集产生了重要的、以前未被认识到的限制。对该模型的大参数空间进行了更广泛的研究。

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 is necessary to use a 3D couplon model to simulate the propagated local releases responsible for calcium clock action. The new 3D algorithm, combining the full couplon model with a spatially resolved cytosolic space using an operator splitting method, has now been completed and demonstrates the local and global propagation of local calcium releases (LCRs) in simulated sino-atrial node cells. The model now explicitly includes coupling to a full set of surface membrane currents, and demonstrates the Lakatta-Maltsev mechanism by which LCRs can drive the spontaneous action potential rhythm of these pacemaker cells. Preliminary results show that this mechanism, together with the presumed role of local SR calcium depletion to terminate release, places significant and previously unrecognized constraints on the placement and clustering of ryanodine receptors in these cells. A more general study of the large parameter space of this model is underway.