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 Ca ²⁺ 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.