The regulation of excitation-contraction coupling in 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 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.