title: Functional interaction between S1 and S4 segments in voltage-gated sodium channels revealed by human channelopathies.
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.
authors.affiliation: a Department of Clinical Research ; University of Bern ; Bern , Switzerland.
authors.forename: Mohamed-Yassine
authors.initials: MY
authors.lastname: Amarouch
authors.forename: Marina A
authors.initials: MA
authors.lastname: Kasimova
authors.forename: Mounir
authors.initials: M
authors.lastname: Tarek
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
mesh_terms: D053447:Channelopathies / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D061566:Voltage-Gated Sodium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D061566:Voltage-Gated Sodium Channels
keywords: S1-S2 segments; cellular electrophysiology; channelopathies; molecular dynamics; sodium channels; voltage-sensing domain