ArticleRedox biology2017
Cysteine residues 244 and 458-459 within the catalytic subunit of Na,K-ATPase control the enzyme's hydrolytic and signaling function under hypoxic conditions.
Article in Redox biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 33 citations in OpenAlex.
- Oral digoxin effects on exercise performance, KThe Journal of physiology · 2022Trial
- Mechanisms mediating effects of cardiotonic steroids in mammalian blood cells.Frontiers in pharmacology · 2025Review
- Impact of the diverse cardiotonic steroids on beta-amyloid precursor protein level.Frontiers in pharmacology · 2025Article
- Na,K-ATPase mediated and cardiotonic induced signaling in health and disease.Frontiers in physiology · 2025Review
- The effect of cytochrome c on Na,K-ATPase.Journal of bioenergetics and biomembranes · 2024Article
- Antioxidant Therapy Reduces Oxidative Stress, Restores Na,K-ATPase Function and Induces Neuroprotection in Rodent Models of Seizure and Epilepsy: A Systematic Review and Meta-Analysis.Antioxidants (Basel, Switzerland) · 2023Review
- Hypoxic Stress-Dependent Regulation of Na,K-ATPase in Ischemic Heart Disease.International journal of molecular sciences · 2023Review
- iHypoxia: An Integrative Database of Protein Expression Dynamics in Response to Hypoxia in Animals.Genomics, proteomics & bioinformatics · 2023Article
- Article
- Role of NaJournal of molecular medicine (Berlin, Germany) · 2022Review
- Rare Anemias: Are Their Names Just Smoke and Mirrors?Frontiers in physiology · 2021Article
- A novel approach for predicting protein S-glutathionylation.BMC bioinformatics · 2020Article
- The Redox-Sensitive Na/K-ATPase Signaling in Uremic Cardiomyopathy.International journal of molecular sciences · 2020Review
- Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling.International journal of molecular sciences · 2019Article
- Glutathione-related substances maintain cardiomyocyte contractile function in hypoxic conditions.Scientific reports · 2019Article
- RNases Disrupt the Adaptive Potential of Malignant Cells: Perspectives for Therapy.Frontiers in pharmacology · 2019Article
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
Our previous findings suggested that reversible thiol modifications of cysteine residues within the actuator (AD) and nucleotide binding domain (NBD) of the Na,K-ATPase may represent a powerful regulatory mechanism conveying redox- and oxygen-sensitivity of this multifunctional enzyme. S-glutathionylation of Cys244 in the AD and Cys 454-458-459 in the NBD inhibited the enzyme and protected cysteines' thiol groups from irreversible oxidation under hypoxic conditions. In this study mutagenesis approach was used to assess the role these cysteines play in regulation of the Na,K-ATPase hydrolytic and signaling functions. Several constructs of mouse α1 subunit of the Na,K-ATPase were produced in which Cys244, Cys 454-458-459 or Cys 244-454-458-459 were replaced by alanine. These constructs were expressed in human HEK293 cells. Non-transfected cells and those expressing murine α1 subunit were exposed to hypoxia or treated with oxidized glutathione (GSSG). Both conditions induced inhibition of the wild type Na,K-ATPase. Enzymes containing mutated mouse α1 lacking Cys244 or all four cysteines (Cys 244-454-458-459) were insensitive to hypoxia. Inhibitory effect of GSSG was observed for wild type murine Na,K-ATPase, but was less pronounced in Cys454-458-459Ala mutant and completely absent in the Cys244Ala and Cys 244-454-458-459Ala mutants. In cells, expressing wild type enzyme, ouabain induced activation of Src and Erk kinases under normoxic conditions, whereas under hypoxic conditions this effect was inversed. Cys454-458-459Ala substitution abolished Src kinase activation in response to ouabain treatment, uncoupled Src from Erk signaling, and interfered with O
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