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 Ca(2+) is severely impaired resulting in abnormal Ca(2+) cycling and excitation-contraction (EC) coupling. Recently, it has been proposed that "leaky" ryanodine receptors (RyRs) contribute to diminished Ca(2+) levels in the SR. Various groups have experimentally investigated the effects of RyR phosphorylation mediated by Ca(2+)/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 Ca(2+). 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 Ca(2+) channels (LCCs) in the cardiac dyad. In this model, it is assumed that upon phosphorylation, RyR Ca(2+)-sensitivity is increased. Individual RyR phosphorylation is modeled as a function of dyadic CaMKII activity, which is modulated by local Ca(2+) levels. The model is constrained by experimental measurements of Ca(2+) 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.
Hashambhoy
Yasmin L
YL
Institute for Computational Medicine, Center for Cardiovascular Bioinformatics and Modeling, The Johns Hopkins University, Baltimore, MD, USA.
Greenstein
Joseph L
JL
Winslow
Raimond L
RL
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D003198:Computer Simulation; D004285:Dogs; D056966:Excitation Contraction Coupling / Q000502:physiology*; D032342:Muscle Cells / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
D019837:Ryanodine Receptor Calcium Release Channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium