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Changes of Resurgent Na(+) Currents in the Na(v)1.4 Channel Resulting from an SCN4A Mutation Contributing to Sodium Channel Myotonia

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 voltage-gated sodium channel Na(v)1.4 have been reported to be responsible for sodium channel myotonia (SCM). The Na(v)1.4 c...

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Autores principales: Huang, Chiung-Wei, Lai, Hsing-Jung, Lin, Pi-Chen, Lee, Ming-Jen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177622/
https://www.ncbi.nlm.nih.gov/pubmed/32276507
http://dx.doi.org/10.3390/ijms21072593
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author Huang, Chiung-Wei
Lai, Hsing-Jung
Lin, Pi-Chen
Lee, Ming-Jen
author_facet Huang, Chiung-Wei
Lai, Hsing-Jung
Lin, Pi-Chen
Lee, Ming-Jen
author_sort Huang, Chiung-Wei
collection PubMed
description 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 voltage-gated sodium channel Na(v)1.4 have been reported to be responsible for sodium channel myotonia (SCM). The Na(v)1.4 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 Na(v)1.4 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 Na(v)1.4 channel’s co-expression with the Na(v)β4 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 Na(v)1.4 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.
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spelling pubmed-71776222020-04-28 Changes of Resurgent Na(+) Currents in the Na(v)1.4 Channel Resulting from an SCN4A Mutation Contributing to Sodium Channel Myotonia Huang, Chiung-Wei Lai, Hsing-Jung Lin, Pi-Chen Lee, Ming-Jen Int J Mol Sci Article 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 voltage-gated sodium channel Na(v)1.4 have been reported to be responsible for sodium channel myotonia (SCM). The Na(v)1.4 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 Na(v)1.4 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 Na(v)1.4 channel’s co-expression with the Na(v)β4 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 Na(v)1.4 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. MDPI 2020-04-08 /pmc/articles/PMC7177622/ /pubmed/32276507 http://dx.doi.org/10.3390/ijms21072593 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Chiung-Wei
Lai, Hsing-Jung
Lin, Pi-Chen
Lee, Ming-Jen
Changes of Resurgent Na(+) Currents in the Na(v)1.4 Channel Resulting from an SCN4A Mutation Contributing to Sodium Channel Myotonia
title Changes of Resurgent Na(+) Currents in the Na(v)1.4 Channel Resulting from an SCN4A Mutation Contributing to Sodium Channel Myotonia
title_full Changes of Resurgent Na(+) Currents in the Na(v)1.4 Channel Resulting from an SCN4A Mutation Contributing to Sodium Channel Myotonia
title_fullStr Changes of Resurgent Na(+) Currents in the Na(v)1.4 Channel Resulting from an SCN4A Mutation Contributing to Sodium Channel Myotonia
title_full_unstemmed Changes of Resurgent Na(+) Currents in the Na(v)1.4 Channel Resulting from an SCN4A Mutation Contributing to Sodium Channel Myotonia
title_short Changes of Resurgent Na(+) Currents in the Na(v)1.4 Channel Resulting from an SCN4A Mutation Contributing to Sodium Channel Myotonia
title_sort changes of resurgent na(+) currents in the na(v)1.4 channel resulting from an scn4a mutation contributing to sodium channel myotonia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177622/
https://www.ncbi.nlm.nih.gov/pubmed/32276507
http://dx.doi.org/10.3390/ijms21072593
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