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

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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.