A model of graded calcium release and L-type Ca channel inactivation in cardiac muscle

Bondarenko, Vladimir E., Glenna C. L. Bett, and Randall L. Rasmusson. A model of graded calcium release and L-type Ca channel inactivation in cardiac muscle. Am J Physiol Heart Circ Physiol 286: H1154–H1169, 2004;10.1152/ajpheart.00168.2003.—We have developed a model of Ca handling in ferret ventricular myocytes. This model includes a novel L-type Ca channel, detailed intracellular Ca movements, and graded Ca -induced Ca release (CICR). The model successfully reproduces data from voltage-clamp experiments, including voltageand time-dependent changes in intracellular Ca concentration ([Ca ]i), L-type Ca channel current (ICaL) inactivation and recovery kinetics, and Ca sparks. The development of graded CICR is critically dependent on spatial heterogeneity and the physical arrangement of calcium channels in opposition to ryanodine-sensitive release channels. The model contains spatially distinct subsystems representing the subsarcolemmal regions where the junctional sarcoplasmic reticulum (SR) abuts the T-tubular membrane and where the L-type Ca channels and SR ryanodine receptors (RyRs) are localized. There are eight different types of subsystems in our model, with between one and eight L-type Ca channels distributed binomially. This model exhibits graded CICR and provides a quantitative description of Ca dynamics not requiring Monte-Carlo simulations. Activation of RyRs and release of Ca from the SR depend critically on Ca entry through L-type Ca channels. In turn, Ca channel inactivation is critically dependent on the release of stored intracellular Ca . Inactivation of ICaL depends on both transmembrane voltage and local [Ca ]i near the channel, which results in distinctive inactivation properties. The molecular mechanisms underlying many ICaL gating properties are unclear, but [Ca ]i dynamics clearly play a fundamental role.