Microstructure-Based Monte Carlo Simulation of Ca²⁺ Dynamics Evoking Cardiac Calcium Channel Inactivation

Abstract

Ca²⁺ dynamics underlying cardiac excitation-contraction coupling are essential for the heart functions. In this study, we constructed microstructure based models of Ca²⁺ dynamics to simulate Ca²⁺ influx through individual L-type Ca²⁺ channels (LCCs), an effective Ca²⁺ diffusion within the cytoplasmic space and in the dyadic space, and the experimentally observed calcium-dependent inactivation (CDI) of the LCCs induced by local and global Ca²⁺ sensing. The models consisted of LCCs with distal and proximal Ca²⁺ (Calmodulin-Ca²⁺ complex) binding sites. In one model, the intra-cellular space was organelle-free cytoplasmic space, and the other was with a dyadic space including sarcoplasmic reticulum membrane. The Ca²⁺ dynamics and CDI of the LCCs in the model with and without the dyadic space were then simulated using the Monte Carlo method. We first showed that an appropriate set of parameter values of the models with effectively extra-slow Ca²⁺ diffusion enabled the models to reproduce major features of the CDI process induced by the local and global sensing of Ca²⁺ near LCCs as measured with single and spatially separated two LCCs by Imredy and Yue (Neuron. 1992;9:197-207). The effective slow Ca²⁺ diffusion might be due to association and dissociation of Ca²⁺ and Calmodulin (CaM). We then examined how the local and global CDIs were affected by the presence of the dyadic space. The results suggested that, in microstructure modeling of Ca²⁺ dynamics in cardiac myocytes, one should take into account the effective Ca²⁺ diffusion under CaM-Ca²⁺ interaction, nanodomain structure of LCCs for detailed CDI, and the geometry of sub-cellular space for modeling dyadic space.