A computational model of Ca²⁺/calmodulin-dependent kinase II in cardiac myocyte

Abstract

The intracellular Ca²⁺ dynamics is modulated in the cardiac myocytes according to the rate of stimulation, and this property contributes to the accelerated relaxation during diastole with increasing heart rate. The Ca²⁺/calmodulin-dependent protein kinase II (CaMKIIδ) may have a central role in adjustment of this frequency dependent modification of the intracellular Ca²⁺ dynamics, but detailed mechanisms remain unclear. Therefore, we prepared a computational CaMKII model which well reproduces the kinetics of CaMKII-Ca²⁺/calmodulin interaction and the frequency dependency of CaMKII autophosphorylation described in vitro experiments. In order to predict CaMKII dynamics and mechanism of Ca²⁺ dynamics regulation in vivo, we incorporate this model into cardiomyocyte model of guinea pig, KyotoModel. In this model, CaMKII is set to phosphorylate L-type Ca²⁺ channel, RyR channel, phospholamban, and SERCA pump. In consistency with experimental data, the amplitude of cytosolic Ca²⁺ transient becomes larger and the decay phase was accelerated in parallel with the frequency-dependent activation of CaMKII. From these simulation data, the mechanism governing the frequency dependency of contraction in cardiomyocytes will be discussed. [J Physiol Sci. 2007;57 Suppl:S197]