Stochastic Simulation of Excitation-Contraction Coupling

上一个项目期间的工作总结 期间，我们开发了新的、功能更强大的蒙特卡罗模拟 算法，以模拟骨骼肌的局部控制。AS 计划，这些方法现在已经被适应和推广到 心脏兴奋收缩偶联。有必要发展 L型钙通道的一种新的门控方案 二氢吡啶受体，DHPR)，因为还没有发表过 此通道的选通方案与 L型钙依赖失活的实验数据 电流和门控电荷运动。初步结果： 心脏ECC的随机模拟表明，局部控制可以在 事实，解释了SR钙释放的阶段性和稳定性，以及 可以对测量的肌浆网钙释放速率进行定量建模 我们的实验室使用了新的俄勒冈州绿色/EGTA技术。这个 模拟还证明了几种类型的 不同DHPR之间竞争释放SR钙， 这可以解释以前出版的令人费解的特点 几个实验室心脏内皮细胞偶联的实验数据。 然而，出现了一个新的悖论：该模型只是证明了 充分的局部和全局稳定性，如果我们假设 心脏兰尼定的足够强大的失活过程 受体，以及更多的 而不是一个钙离子--这些特征还没有令人信服 在离体心RyR门控研究中的应用 双层的。这导致了一种假设，即RyR的门控在 活体与体外有很大的不同，可能是结果 的足突之间的变构相互作用 频道。

SUMMARY OF WORK During the last project period, we developed new, more powerful Monte Carlo simulation algorithms in order to model local control in skeletal muscle. As planned, these methods have now been adapted and extended to cardiac excitation-contraction coupling. It was necessary to develop a new gating scheme for the L-type calcium channel (also known as dihydropyridine receptor, DHPR), since none of the published gating schemes for this channel were consistent with the experimental data on both calcium-dependent inactivation of L-type current and gating charge movement. Preliminary results of stochastic simulation of cardiac ECC show that local control can, in fact, explain the gradation and stability of SR calcium release, and can model quantitatively the rate of SR calcium release measured in our laboratory using the new Oregon green/EGTA technique. The simulations also demonstrate the existence of several types of competition between different DHPR's to release SR calcium, which can explain previously puzzling features of the published experimental data on cardiac EC coupling from several laboratories. However, a new paradox has arisen: the model only demonstrates adequate local and global stability if we assume the existence of a sufficiently powerful inactivation process of the cardiac ryanodine receptor, as well as cooperative activation of this channel by more than one calcium ion--features that have not been convincingly demonstrated in studies of isolated cardiac RyR gating in lipid bilayers. This has led to the hypothesis that the gating of RyR's in vivo is significantly different from that in vitro, possibly as a result of allosteric interactions between the foot processes of neighboring channels.