The regulation of excitation-contraction coupling in cardiac muscle

心肌兴奋-收缩耦合的调节

• 批准号: 341980-2007
• 负责人: Pape, Paul
• 金额: $ 2.19万
• 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: 2009
• 资助国家: 加拿大
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=429975
• 关键词: regulation; excitation; contraction; coupling; cardiac

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.

在骨骼肌和心肌中，当动作电位通过T系统传播时，收缩开始，T系统是表面膜进入肌肉细胞内部的延伸。 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，其然后以某种方式激活紧密贴壁的肌浆网（SR）膜中的Ca 2+释放通道。 在骨骼肌中，已经相当确定的是，主要偶联机制涉及DHPR与其相关的SR Ca 2+释放通道之间的物理联系。 在心肌中，传统观点认为主要偶联机制涉及Ca诱导的Ca 2+释放（CICR），这是一种涉及Ca 2+通过DHPR（以其作为L型Ca 2+通道的能力）的机制，随后是Ca与SR Ca 2+释放通道的结合及其随后的激活。 一个实验的目的是评估一个有争议的提议，即心肌中的主要耦合机制实际上是一个电压激活机制，就像在骨骼肌中看到的那样。 其他目的是评估各种钙反馈机制已经被证明是非常重要的控制SR钙释放骨骼肌。 这些包括正反馈和负反馈机制，分别通过Ca结合到SR Ca 2+释放通道上的位点，Ca失活Ca 2+释放和CICR。 在CICR的情况下，该机制与上述不同之处在于Ca的来源是来自SR而不是来自外部溶液。 还将对可能作用于膜内电荷运动信号的Ca反馈机制进行调查-该信号反映了由DHPR执行的电压感测步骤。