The p.I141V-Y168F double mutation abolished the functional effects of the p.I141V mutation in Nav1.4 and Nav1.5 channels, indicating a specific interaction between Y168-S2 and R225-S4.
The study identifies a specific structural interaction between the S2 and S4 segments underlying the biophysical alterations of the p.I141V mutation in voltage-gated sodium channels.
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.
Amarouch et al. (Wed,) conducted a other in Human channelopathies (clinical hyper-excitability phenotypes). p.I141V-Y168F double mutation vs. p.I141V single mutation was evaluated on Functional effects and activation curve shifts. The p.I141V-Y168F double mutation abolished the functional effects of the p.I141V mutation in Nav1.4 and Nav1.5 channels, indicating a specific interaction between Y168-S2 and R225-S4.