Stochastic Simulation of Excitation-Contraction Coupling

在上一个项目期间，我们开发了一种算法来模拟心脏兴奋-收缩耦合的随机局部控制。由于可用的计算能力，这些模拟大多是使用简化版的算法进行的，该算法忽略了钙离子在双结间隙中的扩散动力学，因此也无法考虑局部钙缓冲液和钙离子通过通道的双向通量的影响。在本项目期间，对算法进行了重新编码，利用MPI（消息传递接口）系统，使通过快速以太网连接的多个工作站之间并行分配计算成为可能。这种重大的重新开发使计算速度提高了10倍，这使得使用完全动态扩散模拟变得可行。动态扩散的研究正在进行中，已经证实局部钙通过缝隙扩散的时间依赖性对激发-收缩耦合的宏观行为有重要影响，包括内源性ATP在内的固定和扩散钙缓冲液都有主要影响。最重要的是，模拟结果表明，SR钙释放通量响应于l型肌上皮钙通道的短暂尾电流，其特征直接反映了钙诱导钙释放（CICR）在双胞内ryanodine受体之间的扩散动力学。这是我们以前在实验中观察到的特征，但没有意识到它的重要性。模拟预测，这种特征可以用外源性扩散缓冲液来操纵，这将使一系列实验成为可能，这些实验可以直接探测局部再生CICR，这是心脏EC耦合的核心。

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.