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J Cereb Blood Flow Metab. 2019 Feb 28:271678X19833757. doi: 10.1177/0271678X19833757. [Epub ahead of print]

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

Author information

1
1 Department of Experimental Neurology, Charité-University Medicine Berlin, Berlin, Germany.
2
2 Center for Stroke Research, Charité-University Medicine Berlin, Berlin, Germany.
3
3 Department of Neurosurgery, Hannover Medical School, Hannover, Germany.
4
4 Research Center and Department of Physiology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
5
5 Department of Neurology, Charité-University Medicine Berlin, Berlin, Germany.
6
6 Bernstein Center for Computational Neuroscience Berlin, Berlin, Germany.
7
7 Einstein Center for Neurosciences Berlin, Berlin, Germany.

Abstract

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.

KEYWORDS:

K-ATPase; Na; Spreading depolarization; familial hemiplegic migraine; knock-out mouse model; spreading depression

PMID:
30819023
DOI:
10.1177/0271678X19833757

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