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

骨骼肌和心肌兴奋-收缩耦合的调节

• 批准号: 341980-2012
• 负责人: Pape, Paul
• 金额: $ 1.89万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=527548
• 关键词: regulation; excitation; contraction; coupling; skeletal

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.

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T管膜上的电压感应器蛋白，然后以某种方式激活紧密相对的肌浆网(SR)中的钙(Ca)释放通道，SR是细胞内储存钙的隔室。钙的释放会引发肌肉收缩。在骨骼肌中，已经很好地确定了主要的耦合机制涉及电压传感器及其相关的SR Ca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，这是一种通过电压传感器的钙流动机制，其能力是L型钙通道。进入细胞内的钙通过CICR结合并激活SR钙释放通道。一个目标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与骨骼肌类似的电压激活机制。其他目的是量化各种钙反馈机制，这些机制已经被证明在控制骨骼肌SR钙释放方面非常重要。这些机制包括：通过与肌浆网钙释放通道上的钙结合作用实现肌浆网钙释放的正反馈机制，以及钙失活钙释放和CICR的负反馈机制。另一个目的是确定最近提出的两种机制中的哪一种是终止心肌细胞内钙释放的主要机制，钙失活和终止是通过SR中主要的钙缓冲蛋白Calequestrin作为SR中[Ca]的传感器/转导来实现的。主要目的是为了更好地了解在生理条件下肌质网钙释放是如何在心肌中被调节的。预计这一知识对于更好地理解在病理生理条件下可能发生的事情是重要的，例如被认为是导致心力衰竭后期心脏收缩能力下降的SR-Ca释放减少。