A simplified local control model of calcium-induced calcium release in cardiac ventricular myocytes.
Calcium (Ca2+)-induced Ca2+ release (CICR) in cardiac myocytes exhibits high gain and is graded. These properties result from local control of Ca2+ release. Existing local control models of Ca2+ release in which interactions between L-Type Ca2+ channels (LCCs) and ryanodine-sensitive Ca2+ release channels (RyRs) are simulated stochastically are able to reconstruct these properties, but only at high computational cost. Here we present a general analytical approach for deriving simplified models of local control of CICR, consisting of low-dimensional systems of coupled ordinary differential equations, from these more complex local control models in which LCC-RyR interactions are simulated stochastically. The resulting model, referred to as the coupled LCC-RyR gating model, successfully reproduces a range of experimental data, including L-Type Ca2+ current in response to voltage-clamp stimuli, inactivation of LCC current with and without Ca2+ release from the sarcoplasmic reticulum, voltage-dependence of excitation-contraction coupling gain, graded release, and the force-frequency relationship. The model does so with low computational cost.
Mathematical Institute, University of Oxford, Oxford, United Kingdom. hinch@maths.ox.ac.uk
R
R
Hinch
J L
JL
Greenstein
A J
AJ
Tanskanen
L
L
Xu
R L
RL
Winslow
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology*; D003198:Computer Simulation; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D016276:Ventricular Function
D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium