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Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms

The cardiac sodium channel Na(V)1.5, encoded by the SCN5A gene, is responsible for the fast upstroke of the action potential. Mutations in SCN5A may cause sodium channel dysfunction by decreasing peak sodium current, which slows conduction and facilitates reentry-based arrhythmias, and by enhancing...

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Autores principales: Rivaud, Mathilde R, Delmar, Mario, Remme, Carol Ann
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341171/
https://www.ncbi.nlm.nih.gov/pubmed/32251506
http://dx.doi.org/10.1093/cvr/cvaa082
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author Rivaud, Mathilde R
Delmar, Mario
Remme, Carol Ann
author_facet Rivaud, Mathilde R
Delmar, Mario
Remme, Carol Ann
author_sort Rivaud, Mathilde R
collection PubMed
description The cardiac sodium channel Na(V)1.5, encoded by the SCN5A gene, is responsible for the fast upstroke of the action potential. Mutations in SCN5A may cause sodium channel dysfunction by decreasing peak sodium current, which slows conduction and facilitates reentry-based arrhythmias, and by enhancing late sodium current, which prolongs the action potential and sets the stage for early afterdepolarization and arrhythmias. Yet, some Na(V)1.5-related disorders, in particular structural abnormalities, cannot be directly or solely explained on the basis of defective Na(V)1.5 expression or biophysics. An emerging concept that may explain the large disease spectrum associated with SCN5A mutations centres around the multifunctionality of the Na(V)1.5 complex. In this alternative view, alterations in Na(V)1.5 affect processes that are independent of its canonical ion-conducting role. We here propose a novel classification of Na(V)1.5 (dys)function, categorized into (i) direct ionic effects of sodium influx through Na(V)1.5 on membrane potential and consequent action potential generation, (ii) indirect ionic effects of sodium influx on intracellular homeostasis and signalling, and (iii) non-ionic effects of Na(V)1.5, independent of sodium influx, through interactions with macromolecular complexes within the different microdomains of the cardiomyocyte. These indirect ionic and non-ionic processes may, acting alone or in concert, contribute significantly to arrhythmogenesis. Hence, further exploration of these multifunctional effects of Na(V)1.5 is essential for the development of novel preventive and therapeutic strategies.
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spelling pubmed-73411712020-07-13 Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms Rivaud, Mathilde R Delmar, Mario Remme, Carol Ann Cardiovasc Res Spotlight Reviews The cardiac sodium channel Na(V)1.5, encoded by the SCN5A gene, is responsible for the fast upstroke of the action potential. Mutations in SCN5A may cause sodium channel dysfunction by decreasing peak sodium current, which slows conduction and facilitates reentry-based arrhythmias, and by enhancing late sodium current, which prolongs the action potential and sets the stage for early afterdepolarization and arrhythmias. Yet, some Na(V)1.5-related disorders, in particular structural abnormalities, cannot be directly or solely explained on the basis of defective Na(V)1.5 expression or biophysics. An emerging concept that may explain the large disease spectrum associated with SCN5A mutations centres around the multifunctionality of the Na(V)1.5 complex. In this alternative view, alterations in Na(V)1.5 affect processes that are independent of its canonical ion-conducting role. We here propose a novel classification of Na(V)1.5 (dys)function, categorized into (i) direct ionic effects of sodium influx through Na(V)1.5 on membrane potential and consequent action potential generation, (ii) indirect ionic effects of sodium influx on intracellular homeostasis and signalling, and (iii) non-ionic effects of Na(V)1.5, independent of sodium influx, through interactions with macromolecular complexes within the different microdomains of the cardiomyocyte. These indirect ionic and non-ionic processes may, acting alone or in concert, contribute significantly to arrhythmogenesis. Hence, further exploration of these multifunctional effects of Na(V)1.5 is essential for the development of novel preventive and therapeutic strategies. Oxford University Press 2020-07-15 2020-04-06 /pmc/articles/PMC7341171/ /pubmed/32251506 http://dx.doi.org/10.1093/cvr/cvaa082 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Spotlight Reviews
Rivaud, Mathilde R
Delmar, Mario
Remme, Carol Ann
Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms
title Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms
title_full Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms
title_fullStr Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms
title_full_unstemmed Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms
title_short Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms
title_sort heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms
topic Spotlight Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341171/
https://www.ncbi.nlm.nih.gov/pubmed/32251506
http://dx.doi.org/10.1093/cvr/cvaa082
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