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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-63738

Petrushanko, Irina Yu; Yakushev, Sergej; Mitkevich, Vladimir A; Kamanina, Yliya V; Ziganshin, Rustam H; Meng, Xianyu; Anashkina, Anastasiya A; Makhro, Asya; Lopina, Olga D; Gassmann, Max; Makarov, Alexander A; Bogdanova, Anna (2012). S-glutathionylation of the Na,K-ATPase catalytic α subunit is a determinant of the enzyme redox-sensitivity. Journal of Biological Chemistry, 287(38):32195-32205.

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Abstract

Na,K-ATPase is highly sensitive to changes in the redox state, and yet the mechanisms of its redox-sensitivity remain unclear. We have explored the possible involvement of S-glutathionylation of the catalytic α subunit in redox-induced responses. For the first time the presence of S-glutathionylated cysteine residues was shown in the α subunit in duck salt glands, rabbit kidneys, and rat myocardium. Exposure of the Na,K-ATPase to oxidized glutathione (GSSG) resulted in an increase in the number of S-glutathionylated cysteine residues. Increase in S-glutathionylation was associated with dose- and time-dependent suppression of the enzyme function up to its complete inhibition. The enzyme inhibition concurred with S-glutathionylation of the Cys 454, 458, 459 and Cys 244. Upon binding of glutathione to these cysteines the enzyme was unable to interact with adenine nucleotides. Inhibition of the Na,K-ATPase by GSSG did not occur in the presence of ATP at concentration above 0.5 mM. Deglutathionylation of the α subunit catalysed by glutaredoxin or dithiothreitol resulted in restoration of the Na,K-ATPase activity. Oxidation of regulatory cysteines made them inaccessible for glutathionylation, but had no profound effect on the enzyme activity. Regulatory S-glutathionylation of the α subunit was induced in rat myocardium in response to hypoxia, and was associated with oxidative stress and ATP depletion. S-glutathionylation was followed by suppression of the Na,K-ATPase activity. The rat α2 isoform was more sensitive to GSSG than the α1 isoform. Our findings imply that regulatory S-glutathionylation of the catalytic subunit plays a key role in the redox-induced regulation of Na,K-ATPase activity.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2012
Deposited On:24 Jul 2012 10:32
Last Modified:30 Nov 2013 20:02
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Publisher DOI:10.1074/jbc.M112.391094
PubMed ID:22798075
Citations:Web of Science®. Times Cited: 15
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Scopus®. Citation Count: 17

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