Calcium Dependent Release and Its Regulation in Cardiac Myocytes: Mathematical model of the RyR Channel

In cardiac myocytes, the calcium flux through the release channels (Ryanodine Receptors; RyRs) defines the transient changes of intracellular calcium corresponding to the trigger, i.e., the transmembrane calcium current, and therefore determines the dynamics of the contractile function of myocytes on a beat-to-beat basis. A controversy exists related to the exact mechanisms responsible for the activation and termination of calcium release, as well as to the increased leakiness of RyR, which has been reported in association with various heart failure conditions. Our aim was to develop, based on previously published models, a mathematical model of RyR that would describe both the calcium-dependent dynamics and the regulation of the calcium release by calcium/calmodulin dependent kinase II (CaMK). We validate the model by comparing the simulated results to in vivo observations, both under normal and CaMK hyperphosphorylation conditions. Results show that the model describes, in a quantitative way, the functional connection between the calcium trigger and release, the dynamic enzymatic regulation, as well as the role of RyR as a component of the whole myocyte. Our results also suggest that CaMK is an important downstream effector in beta-adrenergic regulation. We conclude that the presented model is a solid component that can be employed in further modeling studies, e. g., to explore the double-edged role of CaMK in various heart failure conditions.