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Alternative Splicing of the Cardiac Sodium Channel Creates Multiple Variants of Mutant T1620K Channels

Alternative splicing creates several Na(v)1.5 transcripts in the mammalian myocardium and in various other tissues including brain, dorsal root ganglia, breast cancer cells as well as neuronal stem cell lines. In total nine Na(v)1.5 splice variants have been discovered. Four of them, namely Na(v)1.5...

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Autores principales: Walzik, Stefan, Schroeter, Annett, Benndorf, Klaus, Zimmer, Thomas
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084281/
https://www.ncbi.nlm.nih.gov/pubmed/21552533
http://dx.doi.org/10.1371/journal.pone.0019188
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author Walzik, Stefan
Schroeter, Annett
Benndorf, Klaus
Zimmer, Thomas
author_facet Walzik, Stefan
Schroeter, Annett
Benndorf, Klaus
Zimmer, Thomas
author_sort Walzik, Stefan
collection PubMed
description Alternative splicing creates several Na(v)1.5 transcripts in the mammalian myocardium and in various other tissues including brain, dorsal root ganglia, breast cancer cells as well as neuronal stem cell lines. In total nine Na(v)1.5 splice variants have been discovered. Four of them, namely Na(v)1.5a, Na(v)1.5c, Na(v)1.5d, and Na(v)1.5e, generate functional channels in heterologous expression systems. The significance of alternatively spliced transcripts for cardiac excitation, in particular their role in SCN5A channelopathies, is less well understood. In the present study, we systematically investigated electrophysiological properties of mutant T1620K channels in the background of all known functional Na(v)1.5 splice variants in HEK293 cells. This mutation has been previously associated with two distinct cardiac excitation disorders: with long QT syndrome type 3 (LQT3) and isolated cardiac conduction disease (CCD). When investigating the effect of the T1620K mutation, we noticed similar channel defects in the background of hNa(v)1.5, hNa(v)1.5a, and hNa(v)1.5c. In contrast, the hNa(v)1.5d background produced differential effects: In the mutant channel, some gain-of-function features did not emerge, whereas loss-of-function became more pronounced. In case of hNa(v)1.5e, the neonatal variant of hNa(v)1.5, both the splice variant itself as well as the corresponding mutant channel showed electrophysiological properties that were distinct from the wild-type and mutant reference channels, hNa(v)1.5 and T1620K, respectively. In conclusion, our data show that alternative splicing is a mechanism capable of generating a variety of functionally distinct wild-type and mutant hNa(v)1.5 channels. Thus, the cellular splicing machinery is a potential player affecting genotype-phenotype correlations in SCN5A channelopathies.
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spelling pubmed-30842812011-05-06 Alternative Splicing of the Cardiac Sodium Channel Creates Multiple Variants of Mutant T1620K Channels Walzik, Stefan Schroeter, Annett Benndorf, Klaus Zimmer, Thomas PLoS One Research Article Alternative splicing creates several Na(v)1.5 transcripts in the mammalian myocardium and in various other tissues including brain, dorsal root ganglia, breast cancer cells as well as neuronal stem cell lines. In total nine Na(v)1.5 splice variants have been discovered. Four of them, namely Na(v)1.5a, Na(v)1.5c, Na(v)1.5d, and Na(v)1.5e, generate functional channels in heterologous expression systems. The significance of alternatively spliced transcripts for cardiac excitation, in particular their role in SCN5A channelopathies, is less well understood. In the present study, we systematically investigated electrophysiological properties of mutant T1620K channels in the background of all known functional Na(v)1.5 splice variants in HEK293 cells. This mutation has been previously associated with two distinct cardiac excitation disorders: with long QT syndrome type 3 (LQT3) and isolated cardiac conduction disease (CCD). When investigating the effect of the T1620K mutation, we noticed similar channel defects in the background of hNa(v)1.5, hNa(v)1.5a, and hNa(v)1.5c. In contrast, the hNa(v)1.5d background produced differential effects: In the mutant channel, some gain-of-function features did not emerge, whereas loss-of-function became more pronounced. In case of hNa(v)1.5e, the neonatal variant of hNa(v)1.5, both the splice variant itself as well as the corresponding mutant channel showed electrophysiological properties that were distinct from the wild-type and mutant reference channels, hNa(v)1.5 and T1620K, respectively. In conclusion, our data show that alternative splicing is a mechanism capable of generating a variety of functionally distinct wild-type and mutant hNa(v)1.5 channels. Thus, the cellular splicing machinery is a potential player affecting genotype-phenotype correlations in SCN5A channelopathies. Public Library of Science 2011-04-28 /pmc/articles/PMC3084281/ /pubmed/21552533 http://dx.doi.org/10.1371/journal.pone.0019188 Text en Walzik et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Walzik, Stefan
Schroeter, Annett
Benndorf, Klaus
Zimmer, Thomas
Alternative Splicing of the Cardiac Sodium Channel Creates Multiple Variants of Mutant T1620K Channels
title Alternative Splicing of the Cardiac Sodium Channel Creates Multiple Variants of Mutant T1620K Channels
title_full Alternative Splicing of the Cardiac Sodium Channel Creates Multiple Variants of Mutant T1620K Channels
title_fullStr Alternative Splicing of the Cardiac Sodium Channel Creates Multiple Variants of Mutant T1620K Channels
title_full_unstemmed Alternative Splicing of the Cardiac Sodium Channel Creates Multiple Variants of Mutant T1620K Channels
title_short Alternative Splicing of the Cardiac Sodium Channel Creates Multiple Variants of Mutant T1620K Channels
title_sort alternative splicing of the cardiac sodium channel creates multiple variants of mutant t1620k channels
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084281/
https://www.ncbi.nlm.nih.gov/pubmed/21552533
http://dx.doi.org/10.1371/journal.pone.0019188
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