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: Mohamed-Yassine Amarouch, Marina A Kasimova, Mounir Tarek, Hugues Abriel
• Journal: Channels (Austin, Tex.) (Channels (Austin)) Vol. 8 Issue 5 Pg. 414-20 ( 2014) ISSN: 1933-6969 [Electronic] United States
• PMID: 25483584 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Voltage-Gated Sodium Channels

Topics

• Channelopathies (genetics, metabolism)
• Humans
• Mutation
• Voltage-Gated Sodium Channels (genetics, metabolism)