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Na(+)/K(+)-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes

Compromised Na(+)/K(+)-ATPase function is associated with the occurrence of spreading depolarization (SD). Mutations in ATP1A2, the gene encoding the α2 isoform of the Na(+)/K(+)-ATPase, were identified in patients with familial hemiplegic migraine type 2 (FHM2), a Mendelian model disease for SD. Th...

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Autores principales: Reiffurth, Clemens, Alam, Mesbah, Zahedi-Khorasani, Mahdi, Major, Sebastian, Dreier, Jens P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025397/
https://www.ncbi.nlm.nih.gov/pubmed/30819023
http://dx.doi.org/10.1177/0271678X19833757
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author Reiffurth, Clemens
Alam, Mesbah
Zahedi-Khorasani, Mahdi
Major, Sebastian
Dreier, Jens P
author_facet Reiffurth, Clemens
Alam, Mesbah
Zahedi-Khorasani, Mahdi
Major, Sebastian
Dreier, Jens P
author_sort Reiffurth, Clemens
collection PubMed
description Compromised Na(+)/K(+)-ATPase function is associated with the occurrence of spreading depolarization (SD). Mutations in ATP1A2, the gene encoding the α2 isoform of the Na(+)/K(+)-ATPase, were identified in patients with familial hemiplegic migraine type 2 (FHM2), a Mendelian model disease for SD. This suggests a distinct role for the α2 isoform in modulating SD susceptibility and raises questions about underlying mechanisms including the roles of other Na(+)/K(+)-ATPase α isoforms. Here, we investigated the effects of genetic ablation and pharmacological inhibition of α1, α2, and α3 on SD using heterozygous knock-out mice. We found that only α2 heterozygous mice displayed higher SD susceptibility when challenged with prolonged extracellular high potassium concentration ([K(+)](o)), a pronounced post SD oligemia and higher SD speed in-vivo. By contrast, under physiological [K(+)](o), α2 heterozygous mice showed similar SD susceptibility compared to wild-type littermates. Deficiency of α3 resulted in increased resistance against electrically induced SD in-vivo, whereas α1 deficiency did not affect SD. The results support important roles of the α2 isoform in SD. Moreover, they suggest that specific experimental conditions can be necessary to reveal an inherent SD phenotype by driving a (meta-) stable system into decompensation, reminiscent of the episodic nature of SDs in various diseases.
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spelling pubmed-70253972020-02-24 Na(+)/K(+)-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes Reiffurth, Clemens Alam, Mesbah Zahedi-Khorasani, Mahdi Major, Sebastian Dreier, Jens P J Cereb Blood Flow Metab Original Articles Compromised Na(+)/K(+)-ATPase function is associated with the occurrence of spreading depolarization (SD). Mutations in ATP1A2, the gene encoding the α2 isoform of the Na(+)/K(+)-ATPase, were identified in patients with familial hemiplegic migraine type 2 (FHM2), a Mendelian model disease for SD. This suggests a distinct role for the α2 isoform in modulating SD susceptibility and raises questions about underlying mechanisms including the roles of other Na(+)/K(+)-ATPase α isoforms. Here, we investigated the effects of genetic ablation and pharmacological inhibition of α1, α2, and α3 on SD using heterozygous knock-out mice. We found that only α2 heterozygous mice displayed higher SD susceptibility when challenged with prolonged extracellular high potassium concentration ([K(+)](o)), a pronounced post SD oligemia and higher SD speed in-vivo. By contrast, under physiological [K(+)](o), α2 heterozygous mice showed similar SD susceptibility compared to wild-type littermates. Deficiency of α3 resulted in increased resistance against electrically induced SD in-vivo, whereas α1 deficiency did not affect SD. The results support important roles of the α2 isoform in SD. Moreover, they suggest that specific experimental conditions can be necessary to reveal an inherent SD phenotype by driving a (meta-) stable system into decompensation, reminiscent of the episodic nature of SDs in various diseases. SAGE Publications 2019-02-28 2020-03 /pmc/articles/PMC7025397/ /pubmed/30819023 http://dx.doi.org/10.1177/0271678X19833757 Text en © The Author(s) 2019 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Articles
Reiffurth, Clemens
Alam, Mesbah
Zahedi-Khorasani, Mahdi
Major, Sebastian
Dreier, Jens P
Na(+)/K(+)-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes
title Na(+)/K(+)-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes
title_full Na(+)/K(+)-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes
title_fullStr Na(+)/K(+)-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes
title_full_unstemmed Na(+)/K(+)-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes
title_short Na(+)/K(+)-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes
title_sort na(+)/k(+)-atpase α isoform deficiency results in distinct spreading depolarization phenotypes
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025397/
https://www.ncbi.nlm.nih.gov/pubmed/30819023
http://dx.doi.org/10.1177/0271678X19833757
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