Stochastic Simulation of Excitation-Contraction Coupling

工作总结在前一个项目期间，我们开发了一种算法来模拟随机局部控制心脏兴奋收缩耦合。 由于可用的计算能力的原因，这些模拟中的大多数是使用简化版本的算法来完成的，该算法忽略了钙离子在二元连接裂隙中的扩散动力学，因此也不能考虑局部钙缓冲液和钙离子通过通道的双向通量的影响。 在此项目期间，算法已被重新编码，以利用MPI（消息传递接口）系统，这使得有可能分布在多个工作站之间通过快速以太网连接的并行计算。 这一重大的重新开发使计算速度提高了10倍，这使得使用完整的动态扩散模拟变得切实可行。 与动态扩散的研究正在进行中，并已证实，时间依赖性的本地钙通过裂缝的传播有一个重要的影响的宏观行为的兴奋-收缩耦合，固定和可扩散的钙缓冲，包括内源性ATP，有重大影响。 最重要的是，模拟结果表明，SR钙释放通量在响应简短的尾电流通过L型肌膜钙通道携带的签名，直接反映了传播的钙诱导的钙释放（CICR）之间的兰尼碱受体在二分体？我们以前在实验中实际上观察到了这个信号，但没有意识到它的重要性。 模拟预测，这种签名可以用外源性可扩散缓冲液来操纵，这将使一系列实验成为可能，这些实验可以直接探测心脏EC耦合的核心的局部再生CICR。

SUMMARY OF WORK During the previous project period we developed an algorithm to simulate stochastic local control of cardiac excitation-contraction coupling. For reasons of available computational power, most of these simulations were done using a simplified version of the algorithm which ignores the dynamics of diffusion of calcium ions in the diadic junctional cleft, and therefore also cannot take into account the effects of local calcium buffers and bi-directional flux of calcium ions through channels. During this project period, the algorithm has been re-coded to make use of the MPI (message passing interface) system which makes it possible to distribute the computations in parallel among multiple workstations linked by fast ethernet. This major redevelopment has resulted in a 10-fold increase in computational speed, which has made it practical to use the full dynamic-diffusion simulation. Studies with dynamic diffusion are underway, and have confirmed that the time-dependence of the spread of local calcium through the cleft has an important effect on the macroscopic behavior of excitation-contraction coupling, and that both fixed and diffusible calcium buffers, including endogenous ATP, have major effects. Most importantly, the simulations showed that SR calcium release fluxe in response to brief tail currents through the L-type sarcolemmal calcium channel carry a signature that directly reflects the dynamics of spread of calcium-induced calcium release (CICR) among the ryanodine receptors in the diad ? a signature which we had actually previously observed experimentally without realizing its significance. Simulations predict that this signature can be manipulated with exogenous diffusible buffers, which will make possible a series of experiments that can directly probe the local regenerative CICR which is at the heart of cardiac EC coupling.