Influence of channel subunit composition on L-type Ca2+ current kinetics and cardiac wave stability

Abstract

Previous studies have demonstrated that the slope of the function relating the action potential duration (APD) and the diastolic interval, known as the APD restitution curve, plays an important role in the initiation and maintenance of ventricular fibrillation. Since the APD restitution slope critically depends on the kinetics of the L-type Ca2+ current, we hypothesized that manipulation of the subunit composition of these channels may represent a powerful strategy to control cardiac arrhythmias. We studied the kinetic properties of the human L-type Ca2+ channel (Cav1.2) coexpressed with the α2δ-subunit alone (α1C + α2δ) or in combination with β2a, β2b, or β3 subunits (α1C + α2δ + β), using Ca2+ as the charge carrier. We then incorporated the kinetic properties observed experimentally into the L-type Ca2+ current mathematical model of the cardiac action potential to demonstrate that the APD restitution slope can be selectively controlled by altering the subunit composition of the Ca2+ channel. Assuming that β2b most closely resembles the native cardiac L-type Ca2+ current, the absence of β, as well as the coexpression of β2a, was found to flatten restitution slope and stabilize spiral waves. These results imply that subunit modification of L-type Ca2+ channels can potentially be used as an antifibrillatory strategy.