Modulation of a Bacterial Voltage-Gated Sodium Channel by the Anti-Epileptic Drug Lacosamide

Abstract

Voltage-gated sodium channels play essential roles in electrical signaling and are primary targets in the treatment of pathologies such as epilepsy. Bacterial sodium channels are known to exhibit similar modulation by anti-epileptic agents, yet the interactions and modulation mechanisms remain unsolved at the molecular level. We have carried out multi-microsecond simulations of the bacterial NavAb channel in the presence of the drug lacosamide, a novel and effective antiepileptic drug which appears to favor slow inactivated states. We have observed drug access to the channel pore via membrane-bound fenestrations, binding to residue F203 that is a surrogate for the highly conserved FS6 in mammalian channels. We also see significant binding at the cytoplasmic gate (N211), as well as interactions with charged Arg side chains throughout entire voltage sensor domains. Calculated dissociation constants reveal that lacosamide has stronger affinity in specific conformations of the pore-forming S6 helices associated with slow inactivation and consistent with experimental evidence from mammalian channels (1). Moreover, we hypothesize that asymmetric binding within the tetrameric channel may instigate pore collapse, helping to explain this state-dependence. These studies provide new insight into sodium channel modulation, and predictions to assist in the development of improved anti-epileptic drugs.1. Errington et al (2008) Mol. Pharm., 73(1), 157-169