Key result
Microstructure-based Monte Carlo simulations demonstrated that effectively slow Ca2+ diffusion and the nanodomain structure of L-type calcium channels are essential for reproducing calcium-dependent inactivation.
Microstructure-based modeling suggests that effective slow Ca2+ diffusion, nanodomain structure of LCCs, and dyadic space geometry are critical for accurately simulating calcium-dependent inactivation in cardiac myocytes.
Supports microstructure-based cardiac modeling; leaves open in vivo validation and clinical translation.
Ca(2+) dynamics underlying cardiac excitation-contraction coupling are essential for heart functions. In this study, we constructed microstructure-based models of Ca(2+) dynamics to simulate Ca(2+) influx through individual L-type Calcium channels (LCCs), an effective Ca(2+) 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 Ca(2+) sensing. The models consisted of LCCs with distal and proximal Ca(2+) (Calmodulin-Ca(2+) 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 Ca(2+) 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 Ca(2+) diffusion enabled the models to reproduce major features of the CDI process induced by the local and global sensing of Ca(2+) near LCCs as measured with single and two spatially separated LCCs by Imredy and Yue (Neuron. 1992;9:197-207). The effective slow Ca(2+) diffusion might be due to association and dissociation of Ca(2+) 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 Ca(2+) dynamics in cardiac myocytes, the effective Ca(2+) diffusion under CaM-Ca(2+) interaction, the nanodomain structure of LCCs for detailed CDI, and the geometry of subcellular space for modeling dyadic space should be considered.
No takes yet. Share an insight, caveat, or question.
Kawazu et al. (2008) studied Cardiac excitation-contraction coupling. Microstructure-based Monte Carlo simulation vs. Simple membrane model without dyadic space was evaluated on Ca2+ dynamics and calcium-dependent inactivation (CDI). Microstructure-based Monte Carlo simulations demonstrated that effectively slow Ca2+ diffusion and the nanodomain structure of L-type calcium channels are essential for reproducing calcium-dependent inactivation.