Modeling of cardiac Ca²⁺ channel inactivation

Abstract

The inactivation of the cardiac L-type Ca²⁺ current is composed of voltage-dependent and calcium-dependent mechanisms. We modeled physiological modulation of inactivation of the current in cardiac ventricular myocytes. Firstly, we used the recent detailed kinetic data for voltage dependent-inactivation (VDI) and its modulation by β-adrenergic stimulation. We modeled VDI based on the experimental data and calcium dependent-inactivation (CDI) as a function of Ca²⁺-influx through L-type Ca²⁺ channels. This model could largely reproduce the behavior of physiological L-type Ca²⁺ channel current carried by divalent cations in the basal as well as under β-adrenergic stimulation. Next, we constructed microstructure based Ca²⁺ dynamics models to simulate Ca²⁺ influx through individual L-type Ca²⁺ channels and diffusion in the dyadic space which would induce CDI. These models used the agent base Monte Carlo method and they consisted of L-type Ca²⁺ channels with distal and proximal Ca²⁺ binding sites, dyadic space, sarcoplasmic reticulum membrane, and free calcium ions. The models reproduced major features of the CDI process which had been measured with single channel recording. The developed models will be useful to estimate the respective roles of VDI and CDI of L-type Ca²⁺ channels in various physiological and pathological conditions of the heart. [J Physiol Sci. 2008;58 Suppl:S46]