The regulation of excitation-contraction coupling in skeletal and cardiac muscle

在骨骼肌和心肌中，当动作电位通过 T 系统（表面膜延伸到肌肉细胞内部）传播时，就会启动收缩。 T 系统的去极化随后会激活 T 管膜中的电压传感器蛋白，然后以某种方式激活紧密相连的肌浆网 (SR) 中的钙 (Ca) 释放通道，肌浆网是一种储存 Ca 的细胞内区室。 释放的钙会引发肌肉收缩。 在骨骼肌中，已相当确定主要耦合机制涉及电压传感器与其相关的 SR Ca 释放通道之间的物理连接。 在心肌中，传统观点认为主要耦合机制涉及 Ca 诱导 Ca 释放 (CICR)，这是一种涉及 Ca 通量通过电压传感器（作为 L 型 Ca 通道）的机制。 进入细胞的 Ca 通过 CICR 结合并激活 SR Ca 释放通道。 一个目标是评估一项有争议的提议，即心肌中的主要耦合机制实际上是类似于骨骼肌中的电压激活机制。 其他目标是量化各种 Ca 反馈机制，这些机制已被证明对于控制骨骼肌 SR Ca 释放非常重要。 这些包括 SR Ca 释放通过 Ca 结合到 SR Ca 释放通道上的位点发挥作用的自身释放的正反馈机制和负反馈机制、Ca 释放的 Ca 失活和 CICR。 另一个目标是确定最近提出的两种机制中哪一种是终止心肌细胞 Ca2+ 释放、Ca2+ 失活和通过 SR 中主要 Ca2+ 缓冲蛋白（calsequestrin）终止的主要机制，作为 SR 中 [Ca2+] 的传感器/转导器。 主要目标是更好地了解生理条件下心肌中 SR Ca 的释放是如何调节的。 预计这些知识对于更好地理解病理生理条件下可能发生的情况非常重要，例如 SR Ca 释放的减少被认为是导致心力衰竭后期心脏收缩力下降的原因。

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 voltage-sensor proteins in the T-tubular membrane which then somehow activate calcium (Ca) release channels in the closely apposed sarcoplasmic reticulum (SR), an intracellular compartment that stores Ca. The released Ca triggers muscle contraction. In skeletal muscle, it is fairly well established that the primary coupling mechanism involves a physical link between the voltage sensor and its associated SR Ca release channel. In cardiac muscle, the traditional view has been that the primary coupling mechanism involves Ca-induced Ca release (CICR), a mechanism involving Ca flux through the voltage sensor in its capacity as an L-type Ca channel. Ca entering the cell binds to and activates SR Ca release channels via CICR. One goal is to evaluate a controversial proposal that the primary coupling mechanism in cardiac muscle is, in fact, a voltage activation mechanism like that in skeletal muscle. Other aims are to quantify various Ca feedback mechanisms already shown to be very important in controlling SR Ca release in skeletal muscle. These include positive and negative feedback mechanisms of SR Ca release on its own release acting via Ca binding to sites on the SR Ca release channels, Ca inactivation of Ca release and CICR, respectively. Another goal is to determine which of two recently proposed mechanisms is the main one responsible for terminating Ca release in cardiac cells, Ca inactivation and termination via the main Ca buffering protein in the SR, calsequestrin, acting as a sensor/transducer of [Ca] in the SR. The main goals are to better understand how SR Ca release is regulated in cardiac muscle under physiological conditions. It is expected that this knowledge should be important in better understanding what might happen under pathophysiological conditions such as the decrease in SR Ca release thought to be responsible for the decreased contractility of heart in later stages of heart failure.