Role of CaMKII in RyR leak, EC coupling and action potential duration: A computational model

During heart failure, the ability of the sarcoplasmic reticulum (SR) to store Ca2+ is severely impaired resulting in abnormal Ca2+ cycling and excitation–contraction (EC) coupling. Recently, it has been proposed that “leaky” ryanodine receptors (RyRs) contribute to diminished Ca2+ levels in the SR. Various groups have experimentally investigated the effects of RyR phosphorylation mediated by Ca2+/calmodulin-dependent kinase II (CaMKII) on RyR behavior. Some of these results are difficult to interpret since RyR gating is modulated by many external proteins and ions, including Ca2+. Here, we present a mathematical model representing CaMKII–RyR interaction in the canine ventricular myocyte. This is an extension of our previous model which characterized CaMKII phosphorylation of L-type Ca2+ channels (LCCs) in the cardiac dyad. In this model, it is assumed that upon phosphorylation, RyR Ca2+-sensitivity is increased. Individual RyR phosphorylation is modeled as a function of dyadic CaMKII activity, which is modulated by local Ca2+ levels. The model is constrained by experimental measurements of Ca2+ spark frequency and steady state RyR phosphorylation. It replicates steady state RyR (leak) fluxes in the range measured in experiments without the addition of a separate passive leak pathway. Simulation results suggest that under physiological conditions, CaMKII phosphorylation of LCCs ultimately has a greater effect on RyR flux as compared with RyR phosphorylation. We also show that phosphorylation of LCCs decreases EC coupling gain significantly and increases action potential duration. These results suggest that LCC phosphorylation sites may be a more effective target than RyR sites in modulating diastolic RyR flux.

Research Highlights
► We present a ventricular myocyte model with local LCC and RyR regulation by CaMKII
► RyR phosphorylation augments ECC gain. LCC phosphorylation reduces gain curve slope
► Phosphorylation of even large fractions of RyRs modestly affects Ca transients
► Diastolic SR leak is increased more by LCC than RyR phosphorylation during APs
► Augmented LCC phosphorylation increases APD and induces EADs