Modeling the Structure and Function of L-Type Calcium Channel (Cav1.2) to Understand its Effect in Cardiac Propagation

Abstract

The gating dynamics of the voltage gated L-type calcium channel (VGLCC) play an important role in intracellular calcium dynamics and the shape of the cardiac action potential. In this work we focus on modeling the structure of the VGLCC at the atomistic level to elucidate its structure-function relationship. using the crystal structure of the wild type voltage gated sodium channel (NavAb) i as the structural template, we propose a model of the Cav1.2 calcium channel. By using Molecular Dynamics simulations of the calcium channel embedded in a model membrane, we have explored the microscopic structure-function relationship of this channel protein. In parallel, we investigated the function of the channel in ventricular propagation dynamics. Our functional goal is to understand the effect of Cav1.2 gating in the ventricular tachycardia to fibrillation transition. With this in mind, we simulated the effect of changing the gating dynamics of the Cav1.2 on two dimensional spiral wave simulations run on a 640x640 grid wherein each node was represented by a Luo-Rudy model of the cardiac cellii. Specifically, we investigated and demonstrated the hypothesis that affecting the time constant of VGLCC inactivation destabilizes spiral wave behavior which is important in the clinical transition from normal rhythm to reentry tachycardia (one spiral) which often degenerates into ventricular fibrillation (multiple spirals). We will present our channel model and its validation to derive hypotheses of how our structure relates to the functional findings.Payandeh J et.al. Crystal structure of a voltage-gated sodium channel in two potentially inactivated states. Nature. 2012 May 20;486(7401):135-9.[1] Luo CH, Rudy Y. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res. 1994 Jun;74(6):1071-96.