Stochastic Simulation Of Excitation-contraction Coupling

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SUMMARY OF WORK The 2D phenomenalogical model has been exercised extensively to generate statistics showing how periodicity of the calcium clock emerges as the RyR calcium release current is increased, allowing the clock to entrain with membrane currents to regulate the heart rate. The results of those simulations have been published in Biophysical Journal. The full Monte-Carlo couplon model with a single cytosolic compartment has been updated to include the effects of local depletion of calcium at individual calcium release terminals of the junctional SR. Simulations of the parallelized model run on Biowulf confirm that local depletion makes a critical contribution to calcium spark termination and that it suffices as the only termination mechanism. However, in that case, there is a critical relationship between the intra-lumenal diffusion rate of SR calcium and the gating kinetics of the RyR that must be satisfied to prevent instability of sparks with delayed termination. Under calcium overload, the single-cytosol couplon model does not osciallate. This makes it clear that it will be necessary to use a 3D couplon model to simulate the propagated local releases responsible for calcium clock action. A new 3D algorithm, combining the full couplon model with a spatially resolved cytosolic space using an operator splitting method is in the final stages of development and will be used to study the way in which calcium releases entrain with membrane currents in a realistic biophysical model.