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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.

SUBMITTER: Amarouch MY

PROVIDER: S-EPMC4594541 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Amarouch Mohamed-Yassine MY Kasimova Marina A MA Tarek Mounir M Abriel Hugues H

Channels (Austin, Tex.) 20140101 5

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. ...[more]

PMID: 25483584

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