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

Abstract

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 Ca2+-induced Ca2+ release (CICR). The model successfully reproduces data from voltage-clamp experiments, including voltage- and time-dependent changes in intracellular Ca2+ concentration ([Ca2+]i), L-type Ca2+ channel current ( ICaL) 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 ICaL depends on both transmembrane voltage and local [Ca2+]i near the channel, which results in distinctive inactivation properties. The molecular mechanisms underlying many ICaL gating properties are unclear, but [Ca2+]i dynamics clearly play a fundamental role.