A model of graded calcium release and L-type Ca2+ channel inactivation in cardiac muscle.
We have developed a model of Ca(2+) handling in ferret ventricular myocytes. This model includes a novel L-type Ca(2+) channel, detailed intracellular Ca(2+) movements, and graded Ca(2+)-induced Ca(2+) release (CICR). The model successfully reproduces data from voltage-clamp experiments, including voltage- and time-dependent changes in intracellular Ca(2+) concentration ([Ca(2+)](i)), L-type Ca(2+) channel current (I(CaL)) inactivation and recovery kinetics, and Ca(2+) 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(2+) 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(2+) channels distributed binomially. This model exhibits graded CICR and provides a quantitative description of Ca(2+) dynamics not requiring Monte-Carlo simulations. Activation of RyRs and release of Ca(2+) from the SR depend critically on Ca(2+) entry through L-type Ca(2+) channels. In turn, Ca(2+) channel inactivation is critically dependent on the release of stored intracellular Ca(2+). Inactivation of I(CaL) depends on both transmembrane voltage and local [Ca(2+)](i) near the channel, which results in distinctive inactivation properties. The molecular mechanisms underlying many I(CaL) gating properties are unclear, but [Ca(2+)](i) dynamics clearly play a fundamental role.
Bondarenko
Vladimir E
VE
Dept. of Physiology and Biophysics, Univ. at Buffalo, SUNY, Buffalo, NY 14214, USA.
Bett
Glenna C L
GC
Rasmusson
Randall L
RL
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D003198:Computer Simulation; D005289:Ferrets; D015640:Ion Channel Gating / Q000502:physiology*; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques
D020746:Calcium Channels, L-Type; D002118:Calcium