Gabapentinoids Suppress Early Afterdepolarizations by Uncoupling α2δ-1 Subunits from CAV1.2 Channels: Implications for CAV Channel Gating-Modifiers as a New Class of Antiarrhythmics

Abstract

Under certain pathological conditions, the repolarization phase of the cardiac action potential (AP) is interrupted by membrane potential oscillations called early afterdepolarizations (EADs), well-recognized triggers of deadly cardiac arrhythmias. The reactivation of L-type calcium current (ICa,L) plays a prominent role in EAD formation. In recent studies using the dynamic clamp technique, we have shown that a small depolarizing shift (<5mV) of the CaV1.2 steady-state activation potently suppresses EAD occurrence. Based on this findings, we hypothesized that pharmacological interventions that induce a depolarizing shift of macroscopic ICa,L activation (gating modifiers) can suppress EADs and their arrhythmogenic consequences. Gabapentinoids (gabapentin and pregabalin), drugs that selectively bind to α2δ-1 CaV subunits and are commonly used to treat epilepsy and neuropathic pain, are good candidates as Cav gating modifiers. We found that gabapentin induced a time-dependent depolarizing shift of the voltage-dependent activation of CaV1.2 channels expressed in Xenopus oocytes (α1C β3 α2δ-1; 1mM gabapentin, 2h incubation). Since α2δ-1 facilitates CaV1.2 voltage-dependent activation, these results suggest a functional uncoupling of α2δ-1 from a fraction of channels. Importantly, the maximal macroscopic conductance was unaltered, implying that CaV1.2 channel trafficking was not perturbed, in contrast to the effects shown in other CaV isoforms. We then studied gabapentinoids effect on EAD susceptibility in freshly-dissociated rabbit ventricular myocytes under EAD-promoting conditions (600μM H2O2). Strikingly, 1 mM pregabalin suppressed EAD occurrence and restored AP duration as predicted based on the depolarizing shift in voltage-dependent activation. Taken together, these results support the view that gabapentinoids, and more generally CaV1.2 gating modifiers, show promise in suppressing EAD-mediated arrhythmias and could constitute a novel class of antiarrhythmics.