CaMKII-induced shift in modal gating explains L-type Ca(2+) current facilitation: a modeling study.
Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays an important role in L-type Ca(2+) channel (LCC) facilitation: the Ca(2+)-dependent augmentation of Ca(2+) current (I(CaL)) exhibited during rapid repeated depolarization. Multiple mechanisms may underlie facilitation, including an increased rate of recovery from Ca(2+)-dependent inactivation and a shift in modal gating distribution from mode 1, the dominant mode of LCC gating, to mode 2, a mode in which openings are prolonged. We hypothesized that the primary mechanism underlying facilitation is the shift in modal gating distribution resulting from CaMKII-mediated LCC phosphorylation. We developed a stochastic model describing the dynamic interactions among CaMKII, LCCs, and phosphatases as a function of dyadic Ca(2+) and calmodulin levels, and we incorporated it into an integrative model of the canine ventricular myocyte. The model reproduces behaviors at physiologic protein levels and allows for dynamic transition between modes, depending on the LCC phosphorylation state. Simulations showed that a CaMKII-dependent shift in LCC distribution toward mode 2 accounted for the I(CaL) positive staircase. Moreover, simulations demonstrated that experimentally observed changes in LCC inactivation and recovery kinetics may arise from modal gating shifts, rather than from changes in intrinsic inactivation properties. The model therefore serves as a powerful tool for interpreting I(CaL) experiments.
Hashambhoy
Yasmin L
YL
Institute for Computational Medicine, Center for Cardiovascular Bioinformatics and Modeling, and the Whitaker Biomedical Engineering Institute, the Johns Hopkins University, Baltimore, Maryland, USA.
Winslow
Raimond L
RL
Greenstein
Joseph L
JL
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D003198:Computer Simulation; D004285:Dogs; D015640:Ion Channel Gating; D008564:Membrane Potentials; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D013269:Stochastic Processes
D020746:Calcium Channels, L-Type; D002147:Calmodulin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D010744:Phosphoric Monoester Hydrolases; D002118:Calcium