A model of graded calcium release and L-type Ca²⁺ channel inactivation in cardiac muscle

We have developed a model of Ca²⁺ handling in ferret ventricular myocytes. This model includes a novel L-type Ca²⁺ channel, detailed intracellular Ca²⁺ movements, and graded Ca ²⁺-induced Ca²⁺ release (CICR). The model successfully reproduces data from voltage-clamp experiments, including voltage- and time-dependent changes in intracellular Ca²⁺ concentration ([Ca ²⁺]_i), L-type Ca²⁺ channel current (I _CaL) inactivation and recovery kinetics, and Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ channels distributed binomially. This model exhibits graded CICR and provides a quantitative description of Ca²⁺ dynamics not requiring Monte-Carlo simulations. Activation of RyRs and release of Ca²⁺ from the SR depend critically on Ca²⁺ entry through L-type Ca²⁺ channels. In turn, Ca²⁺ channel inactivation is critically dependent on the release of stored intracellular Ca²⁺. Inactivation of I_CaL depends on both transmembrane voltage and local [Ca²⁺]_i near the channel, which results in distinctive inactivation properties. The molecular mechanisms underlying many I_CaL gating properties are unclear, but [Ca²⁺] _i dynamics clearly play a fundamental role.