Changes of resurgent Na+ currents in the Nav1.4 channel resulting from an SCN4A mutation contributing to sodium channel myotonia
Journal
International Journal of Molecular Sciences
Journal Volume
21
Journal Issue
7
Pages
2593
ISSN
1661-6596
Date Issued
2020-04-01
Author(s)
Abstract
Myotonia congenita (MC) is a rare disorder characterized by stiffness and weakness of the limb and trunk muscles. Mutations in the SCN4A gene encoding the alpha-subunit of the voltagegated sodium channel Nav1.4 have been reported to be responsible for sodium channel myotonia (SCM). The Nav1.4 channel is expressed in skeletal muscles, and its related channelopathies affect skeletal muscle excitability, which can manifest as SCM, paramyotonia and periodic paralysis. In this study, the missense mutation p.V445M was identified in two individual families with MC. To determine the functional consequences of having a mutated Nav1.4 channel, whole-cell patch-clamp recording of transfected Chinese hamster ovary cells was performed. Evaluation of the transient Na+ current found that a hyperpolarizing shift occurs at both the activation and inactivation curves with an increase of the window currents in the mutant channels. The Nav1.4 channel’s co-expression with the Navβ4 peptide can generate resurgent Na+ currents at repolarization following a depolarization. The magnitude of the resurgent currents is higher in the mutant than in the wild-type (wT) channel. Although the decay kinetics are comparable between the mutant and wT channels, the time to the peak of resurgent Na+ currents in the mutant channel is significantly protracted compared with that in the wT channel. These findings suggest that the p.V445M mutation in the Nav1.4 channel results in an increase of both sustained and resurgent Na+ currents, which may contribute to hyperexcitability with repetitive firing and is likely to facilitate recurrent myotonia in SCM patients. ? 2020, MDPI AG. All rights reserved.
Subjects
Myotonia congenita; Nav1.4; Resurgent current; SCN4A mutation; Sodium channel
SDGs
Other Subjects
sodium channel Nav1.2; sodium channel Nav1.4; sodium channel Nav1.5; sodium ion; tau protein; SCN4A protein, human; sodium channel Nav1.4; Article; CHO-K1 cell line; controlled study; crystal structure; depolarization; electrophysiology; gene; gene mutation; genetic analysis; human; human cell; kinetics; missense mutation; mouse; muscle contraction; muscle rigidity; myotonia; myotonic dystrophy; nonhuman; phenotype; polymerase chain reaction; protein expression; repolarization; sarcoplasmic reticulum; SCN4A gene; sodium current; spinal ganglion; Thomsen disease; Western blotting; whole cell patch clamp; amino acid sequence; animal; Asian continental ancestry group; channelopathy; chemistry; CHO cell line; Cricetulus; female; genetics; male; metabolism; missense mutation; patch clamp technique; pathophysiology; pedigree; physiology; Amino Acid Sequence; Animals; Asian Continental Ancestry Group; Channelopathies; CHO Cells; Cricetulus; Female; Humans; Male; Mutation, Missense; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Pedigree
Publisher
MDPI AG
Type
journal article