Referenced in: none

Automatically associated channels: Nav1.4 , Nav1.5

Title: Functional interaction between S1 and S4 segments in voltage-gated sodium channels revealed by human channelopathies.

Authors: Mohamed-Yassine Amarouch, Marina A Kasimova, Mounir Tarek, Hugues Abriel

Journal, date & volume: Channels (Austin), 2014 , 8, 414-20

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25483584

Abstract
The p.I141V mutation of the voltage-gated sodium channel is associated with several clinical hyper-excitability phenotypes. To understand the structural bases of the p.I141V biophysical alterations, molecular dynamics simulations were performed. These simulations predicted that the p.I141V substitution induces the formation of a hydrogen bond between the Y168 residue of the S2 segment and the R225 residue of the S4 segment. We generated a p.I141V-Y168F double mutant for both the Nav1.4 and Nav1.5 channels. The double mutants demonstrated the abolition of the functional effects of the p.I141V mutation, consistent with the formation of a specific interaction between Y168-S2 and R225-S4. The single p.Y168F mutation, however, positively shifted the activation curve, suggesting a compensatory role of these residues on the stability of the voltage-sensing domain.