The regulation of excitation-contraction coupling in cardiac muscle

在骨骼肌和心肌中，当动作电位通过T系统传播时，收缩就开始了。T系统是表膜延伸到肌肉细胞内部的一种系统。T系统的去极化然后激活跨越T管膜的二氢吡啶受体(DHPR)蛋白，然后以某种方式激活紧密相连的肌浆网(SR)膜上的钙释放通道。在骨骼肌中，已经很好地确定了主要的偶联机制涉及DHPR及其相关的SR钙释放通道之间的物理联系。在心肌中，传统的观点一直认为，主要的偶联机制涉及钙诱导的钙释放(CICR)，这是一种涉及通过DHPR(作为L类型的钙通道)的钙离子流动，然后钙与SR钙释放通道结合并随后激活的机制。一个实验目的是评估一个有争议的提议，即心肌中的主要偶联机制实际上是一种类似于骨骼肌的电压激活机制。其他目的是评估已被证明在控制骨骼肌肌浆网钙离子释放中非常重要的各种钙反馈机制。这些机制包括通过与肌质网钙离子释放通道上的钙结合，钙失活钙释放和CICR的正反馈和负反馈机制。在CICR的情况下，其机理与上面描述的不同，因为钙的来源是SR而不是外部溶液。还将研究作用于膜内电荷运动信号的可能的钙反馈机制--反映DHPR执行的电压传感步骤的信号。

In both skeletal and cardiac muscles, contraction is initiated when an action potential propagates through the T-system - an extension of the surface membrane into the interior of the muscle cell. Depolarization of the T-system then activates dihydropyridine receptor (DHPR) proteins that span the T-tubular membrane which then somehow activate Ca2+ release channels in the closely apposed sarcoplasmic reticulum (SR) membrane. In skeletal muscle, it is fairly well established that the primary coupling mechanism involves a physical link between a DHPR and its associated SR Ca2+ release channel. In cardiac muscle, the traditional view has been that the primary coupling mechanism involves Ca-induced Ca2+ release (CICR), a mechanism involving Ca2+ flux through the DHPR (in its capacity as an L-type Ca2+ channel) followed by binding of Ca to the SR Ca2+ release channel and its subsequent activation. One experimental aim is to evaluate a controversial proposal that the primary coupling mechanism in cardiac muscle is, in fact, a voltage activation mechanism like that seen in skeletal muscle. Other aims are to evaluate various Ca feedback mechanisms already shown to be very important in controlling SR Ca2+ release in skeletal muscle. These include positive and negative feedback mechanisms acting via Ca binding to sites on the SR Ca2+ release channels, Ca inactivation of Ca2+ release and CICR, respectively. In the case of CICR, the mechanism differs from that described above in that the source of Ca is from the SR instead of from the external solution. Investigation will also be carried out on possible Ca-feedback mechanisms acting on the intramembranous charge movement signal - a signal reflecting the voltage-sensing step performed by the DHPRs.