Charge Reversal of the Uppermost Arginine in Sliding Helix S4-I Affects Gating of Cardiac Sodium Channel.

ABSTRACT: Several mutations of the uppermost arginine, R219, in the voltage-sensing sliding helix S4_I of cardiac sodium channel Nav1.5 are reported in the ClinVar databases, but the clinical significance of the respective variants is unknown (VUSs). AlphaFold 3 models predicted a significant downshift of S4_I in the R219C VUS. Analogous downshift S4_I, upon its in silico deactivation, resulted in a salt bridge between R219 and the uppermost glutamate, E161, in helix S2_I. To understand how salt bridge elimination affects biophysical characteristics, we generated mutant channel R219E, expressed it in the HEK293-T cells, and employed the patch-clamp method in a whole-cell configuration. Mutation R219E did not change the peak current density but shortened time t

SUBMITTER: Kulichik OE 

PROVIDER: S-EPMC11766011 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature