Restoration of fast inactivation in an inactivation-defective human heart sodium channel by the cysteine modifying reagent benzyl-MTS: analysis of IFM-ICM mutation

Biochemical and Biophysical Research Communications
Mohamed ChahineR G Kallen

Abstract

It has been suggested that the region linking domain III and IV of voltage-gated sodium channels forms the inactivation gate. A combination of site-directed mutagenesis, cysteine covalent modification, and electrophysiological recording techniques was used to identify the role of the Phe1486, a conserved phenylalanine residue located in the III-IV linker of Na+ channels. This Phe1486 is part of a hydrophobic amino acid cluster (IFM) that was proposed to play an essential role in the fast inactivation of voltage-gated sodium channels. Expression in tsA201 cells of an altered human heart 1 Na+ channel (hH1/F1486C) in which Phe1486 was replaced by a cysteine is associated with the appearance of a residual current, a loss of voltage-dependence of the time constants of inactivation, a shift of the steady-state inactivation to more depolarized voltages, and a recovery from inactivation that is faster than the wild-type hH1. Exposure of the cytoplasmic surface of mutant F1486C to the methanthiosulfonate reagents, MTSEA, MTSET, and MTSES, further disrupted macroscopic inactivation, but exposure to MTSBN completely restores fast inactivation and the voltage-dependence of fast inactivation. These findings support the formulation that the...Continue Reading

Citations

Apr 25, 2000·The Journal of General Physiology·M F SheetsD A Hanck
Dec 4, 2004·The Journal of Physiology·Michael F Sheets, Dorothy A Hanck
Jul 8, 2015·Frontiers in Pharmacology·Michael E O'Leary, Mohamed Chahine
Feb 28, 2006·American Journal of Physiology. Heart and Circulatory Physiology·Yujie ZhuPeter J Lee

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