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系统传播到肌肉细胞内部时，收缩就开始了。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)膜中的钙释放通道。在骨骼肌中，相当明确的是，主要的耦合机制涉及DHPR及其相关的SR钙释放通道之间的物理联系。在心肌中，传统观点认为，钙离子的主要偶联机制包括钙诱导的钙离子释放(CICR)，这是一种通过DHPR(其作为L型钙通道的能力)进行钙离子流动的机制，然后钙与肌浆网钙离子释放通道结合并随后激活。一种与骨骼肌类似的电压激活机制。其他目的是评估已被证明在控制骨骼肌SR钙释放方面非常重要的各种钙反馈机制。这些机制包括分别通过与SR钙释放通道上的位置结合的正反馈机制和负反馈机制，钙失活钙释放和CICR。在CICR的情况下，该机制与上述机制的不同之处在于，钙的来源来自SR而不是来自外部溶液。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.