A Computational Model of the Cardiac Sodium Channel DIII Voltage Sensor: Connecting Molecular Movements to Tissue Dynamics

Abstract

The cardiac Na+ channel is a macromolecular protein complex consisting of 4 domains, each composed of 6 transmembrane subunits. The voltage sensing domains (VSD) on DI - DIV, and in particular the DIII VSD has been shown to be critical in activation, inactivation, channel opening, and local anesthetic antiarrhythmic drug action. To date, computational models of the cardiac Na+ channel only account for current kinetics, which limits their ability to predict how perturbations by mutations and drugs at the molecular level may affect higher dimensional properties in the heart. We began by expanding a computational model of the cardiac Na+ channel, and incorporated voltage clamp fluorometry data on DIII VSD movement; this technique allows one to fluorescently track VSD conformation and correlate VSD kinetics with ionic currents. Our expanded 12-state Markov model of the Na+ channel recapitulates a wide range of current kinetics including steady state availability, steady state activation, deactivation, recovery from inactivation, and mean open time, as well as DIII fluorescent activation and deactivation. Next, we examined two LQT3 mutations, R1626P, and M1652R, which have opposing effects on DIII and have differing sensitivities to the Na+ channel blocker mexelitine. We built computational models of each, and their unique interaction with mexelitine. Our results show that a hyperpolarizing shift in DIII can account for the increased sensitivity of R1626P to mexelitine, and the depolarization seen with M1652R renders it mexelitine insensitive. Our computational models were then used to characterize and track these differential effects on DIII movement on the action potential and coupled virtual tissue. We conclude that DIII represents a novel molecular target and plays a primary role in determining differential sensitivity of certain LQT3 mutations to the local anesthetic mexelitine.