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Biomedicines
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The Role of Na,K-ATPase in Human Health: From Structure to...
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The Role of Na,K-ATPase in Human Health: From Structure to Function

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 14449

Special Issue Editors

Dr. Elizaveta Klimanova

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Guest Editor
Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
Interests: Na,K-ATPase; cardiotonic steroids; endothelium; sodium; potassium; gene expression
Prof. Dr. Olga Lopina

E-Mail Website
Guest Editor
Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
Interests: Na,K-ATPase; cardiotonic steroids; ouabain-induced cell death; hypertension; endothelium; Na+-induced gene expression
Dr. Irina Petrushanko

E-Mail Website
Guest Editor
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
Interests: Na,K-ATPase; redox regulation; S-glutathionylation; hypoxia; cardiotonic steroids; beta-amyloid; molecular mechanisms of protein function regulation

Special Issue Information

Dear Colleagues,

Sixty-five years have passed since Jens Skou discovered Na,K-ATPase, but this amazing enzyme is still the object of the close attention of many researchers. Na,K-ATPase provides the active transport of Na+ and K+ across the plasma membrane of animal cells, and plays an essential role in the Na+-gradient-facilitated transport of other ions and biologically important molecules, such as amino acids, neurotransmitters and nucleotides. In addition, it has been shown that side-by-side with canonical Na+i/K+i-dependent cellular responses, Na,K-ATPase is a signal transducer that can receive signals from various endogenous cardiotonic steroids and trigger different and branched signals through protein–protein interactions that affect transcription, translation, tight junction, cell adhesion and exhibit tissue-specific impact on cell survival and death. The transport and receptor functions of the enzyme are sensitive to oxygen concentrations and the redox status of the cell, and one of the key determinants of the enzyme’s redox sensitivity is S-glutathionylation of the Na,K-ATPase subunits. Dysregulation of Na,K-ATPase functioning has an important impact on numerous human pathological conditions including cancer; chronic kidney disease; preeclampsia; and cardiovascular, metabolic and neurological disorders. Na,K-ATPase is also of great interest in viral biology because it is a prominent therapeutic target in a broad spectrum of viral infections. Understanding the molecular mechanisms of Na,K-ATPase dysfunction in pathologies will allow us to propose new methods for the prevention or correction of these diseases in the future. This Special Issue welcomes original articles and reviews on the role of Na,K-ATPase in the pathogenesis of various human disorders and the molecular mechanisms underlying Na,K-ATPase dysfunction.

Dr. Elizaveta Klimanova
Prof. Dr. Olga Lopina
Dr. Irina Petrushanko
Guest Editors

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Keywords

  • Na,K-ATPase
  • transport function
  • receptor function
  • regulation in health and disease
  • cardiotonic steroids
  • Na+i/K+i imbalance
  • redox regulation
  • post-translational modifications
  • structure
  • oligomerization

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Published Papers (7 papers)

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Research

17 pages, 5016 KiB  
Article
The Na/K-ATPase α1/Src Signaling Axis Regulates Mitochondrial Metabolic Function and Redox Signaling in Human iPSC-Derived Cardiomyocytes
by Liquan Cai, Marco T. Pessoa, Yingnyu Gao, Sidney Strause, Moumita Banerjee, Jiang Tian, Zijian Xie and Sandrine V. Pierre
Biomedicines 2023, 11(12), 3207; https://doi.org/10.3390/biomedicines11123207 - 2 Dec 2023
Cited by 1 | Viewed by 1887
Abstract
Na/K-ATPase (NKA)-mediated regulation of Src kinase, which involves defined amino acid sequences of the NKA α1 polypeptide, has emerged as a novel regulatory mechanism of mitochondrial function in metazoans. Mitochondrial metabolism ensures adequate myocardial performance and adaptation to physiological demand. It is also [...] Read more.
Na/K-ATPase (NKA)-mediated regulation of Src kinase, which involves defined amino acid sequences of the NKA α1 polypeptide, has emerged as a novel regulatory mechanism of mitochondrial function in metazoans. Mitochondrial metabolism ensures adequate myocardial performance and adaptation to physiological demand. It is also a critical cellular determinant of cardiac repair and remodeling. To assess the impact of the proposed NKA/Src regulatory axis on cardiac mitochondrial metabolic function, we used a gene targeting approach in human cardiac myocytes. Human induced pluripotent stem cells (hiPSC) expressing an Src-signaling null mutant (A420P) form of the NKA α1 polypeptide were generated using CRISPR/Cas9-mediated genome editing. Total cellular Na/K-ATPase activity remained unchanged in A420P compared to the wild type (WT) hiPSC, but baseline phosphorylation levels of Src and ERK1/2 were drastically reduced. Both WT and A420P mutant hiPSC readily differentiated into cardiac myocytes (iCM), as evidenced by marker gene expression, spontaneous cell contraction, and subcellular striations. Total NKA α1-3 protein expression was comparable in WT and A420P iCM. However, live cell metabolism assessed functionally by Seahorse extracellular flux analysis revealed significant reductions in both basal and maximal rates of mitochondrial respiration, spare respiratory capacity, ATP production, and coupling efficiency. A significant reduction in ROS production was detected by fluorescence imaging in live cells, and confirmed by decreased cellular protein carbonylation levels in A420P iCM. Taken together, these data provide genetic evidence for a role of NKA α1/Src in the tonic stimulation of basal mitochondrial metabolism and ROS production in human cardiac myocytes. This signaling axis in cardiac myocytes may provide a new approach to counteract mitochondrial dysfunction in cardiometabolic diseases. Full article
(This article belongs to the Special Issue The Role of Na,K-ATPase in Human Health: From Structure to Function)
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19 pages, 4074 KiB  
Article
Ouabain Reverts CUS-Induced Disruption of the HPA Axis and Avoids Long-Term Spatial Memory Deficits
by Jacqueline Alves Leite, Ana Maria Orellana, Diana Zukas Andreotti, Amanda Midori Matumoto, Natacha Medeiros de Souza Ports`, Larissa de Sá Lima, Elisa Mitiko Kawamoto, Carolina Demarchi Munhoz and Cristoforo Scavone
Biomedicines 2023, 11(4), 1177; https://doi.org/10.3390/biomedicines11041177 - 14 Apr 2023
Viewed by 1930
Abstract
Ouabain (OUA) is a cardiotonic steroid that modulates Na+, K+ -ATPase activity. OUA has been identified as an endogenous substance that is present in human plasma, and it has been shown to be associated with the response to acute stress in both animals [...] Read more.
Ouabain (OUA) is a cardiotonic steroid that modulates Na+, K+ -ATPase activity. OUA has been identified as an endogenous substance that is present in human plasma, and it has been shown to be associated with the response to acute stress in both animals and humans. Chronic stress is a major aggravating factor in psychiatric disorders, including depression and anxiety. The present work investigates the effects of the intermittent administration of OUA (1.8 μg/kg) during the chronic unpredictable stress (CUS) protocol in a rat’s central nervous system (CNS). The results suggest that the intermittent OUA treatment reversed CUS-induced HPA axis hyperactivity through a reduction in (i) glucocorticoids levels, (ii) CRH-CRHR1 expression, and by decreasing neuroinflammation with a reduction in iNOS activity, without interfering with the expression of antioxidant enzymes. These changes in both the hypothalamus and hippocampus may reflect in the rapid extinction of aversive memory. The present data demonstrate the ability of OUA to modulate the HPA axis, as well as to revert CUS-induced long-term spatial memory deficits. Full article
(This article belongs to the Special Issue The Role of Na,K-ATPase in Human Health: From Structure to Function)
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15 pages, 3014 KiB  
Article
Effect of Ouabain on Glutamate Transport in the Hippocampus of Rats with LPS-Induced Neuroinflammation
by Israel José Pereira Garcia, Paula Fernanda Kinoshita, Jéssica Martins de Moura Valadares, Luciana Estefani Drumond de Carvalho, Vanessa Faria Cortes, Leandro Augusto Barbosa, Cristoforo Scavone and Hérica de Lima Santos
Biomedicines 2023, 11(3), 920; https://doi.org/10.3390/biomedicines11030920 - 16 Mar 2023
Cited by 2 | Viewed by 2023
Abstract
A lipopolysaccharide (LPS)-induced neuroinflammation rat model was used to study the effects of ouabain (OUA) at low concentrations, which can interact with the Na,K-ATPase, causing the modulation of intracellular signalling pathways in the Central Nervous System. Our study aimed to analyse the effects [...] Read more.
A lipopolysaccharide (LPS)-induced neuroinflammation rat model was used to study the effects of ouabain (OUA) at low concentrations, which can interact with the Na,K-ATPase, causing the modulation of intracellular signalling pathways in the Central Nervous System. Our study aimed to analyse the effects of OUA on glutamate transport in the hippocampus of rats with LPS-induced neuroinflammation. Adult male Wistar rats were divided into four groups: OUA (1.8 µg/kg), saline (CTR), LPS (200 µg/kg), and OUA + LPS (OUA 20 min before LPS). The animals were sacrificed after 2 h, and the hippocampus was collected for analysis. After treatment, we determined the activities of Na,K-ATPase and glutamine synthetase (GS). In addition, expression of the α1, α2, and α3 isoforms of Na,K-ATPase and the glutamate transporters, EAAT1 and EAAT2, were also analysed. Treatment with OUA caused a specific increase in the α2 isoform expression (~20%), whereas LPS decreased its expression (~22%), and treatment with OUA before LPS prevented the effects of LPS. Moreover, LPS caused a decrease of approximately 50% in GS activity compared with that in the CTR group; however, OUA pre-treatment attenuated this effect of LPS. Notably, it was found that treatment with OUA caused an increase in the expression of EAAT1 (~30%) and EAAT2 (~25%), whereas LPS caused a decrease in the expression of EAAT1 (~23%) and EAAT2 (~25%) compared with that in the CTR group. When treated with OUA, the effects of LPS were abrogated. In conclusion, the OUA pre-treatment abolished the effect caused by LPS, suggesting that this finding may be related to the restoration of the interaction between FXYD2 and the studied membrane proteins. Full article
(This article belongs to the Special Issue The Role of Na,K-ATPase in Human Health: From Structure to Function)
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19 pages, 3290 KiB  
Article
Augmented Ouabain-Induced Vascular Response Reduces Cardiac Efficiency in Mice with Migraine-Associated Mutation in the Na+, K+-ATPase α2-Isoform
by Rajkumar Rajanathan, Tina Myhre Pedersen, Halvor Osterby Guldbrandsen, Lenette Foldager Olesen, Morten B. Thomsen, Hans Erik Bøtker and Vladimir V. Matchkov
Biomedicines 2023, 11(2), 344; https://doi.org/10.3390/biomedicines11020344 - 25 Jan 2023
Cited by 3 | Viewed by 2250
Abstract
Heterozygous mice (α2+/G301R mice) for the migraine-associated mutation (G301R) in the Na+,K+-ATPase α2-isoform have decreased expression of cardiovascular α2-isoform. The α2+/G301R mice exhibit a pro-contractile vascular phenotype associated with decreased left [...] Read more.
Heterozygous mice (α2+/G301R mice) for the migraine-associated mutation (G301R) in the Na+,K+-ATPase α2-isoform have decreased expression of cardiovascular α2-isoform. The α2+/G301R mice exhibit a pro-contractile vascular phenotype associated with decreased left ventricular ejection fraction. However, the integrated functional cardiovascular consequences of this phenotype remain to be addressed in vivo. We hypothesized that the vascular response to α2-isoform-specific inhibition of the Na+,K+-ATPase by ouabain is augmented in α2+/G301R mice leading to reduced cardiac efficiency. Thus, we aimed to assess the functional contribution of the α2-isoform to in vivo cardiovascular function of wild-type (WT) and α2+/G301R mice. Blood pressure, stroke volume, heart rate, total peripheral resistance, arterial dP/dt, and systolic time intervals were assessed in anesthetized WT and α2+/G301R mice. To address rate-dependent cardiac changes, cardiovascular variables were compared before and after intraperitoneal injection of ouabain (1.5 mg/kg) or vehicle during atrial pacing. The α2+/G301R mice showed an enhanced ouabain-induced increase in total peripheral resistance associated with reduced efficiency of systolic development compared to WT. When the hearts were paced, ouabain reduced stroke volume in α2+/G301R mice. In conclusion, the ouabain-induced vascular response was augmented in α2+/G301R mice with consequent suppression of cardiac function. Full article
(This article belongs to the Special Issue The Role of Na,K-ATPase in Human Health: From Structure to Function)
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18 pages, 3402 KiB  
Article
Mesenchymal Stem/Stromal Cells in Three-Dimensional Cell Culture: Ion Homeostasis and Ouabain-Induced Apoptosis
by Alla N. Shatrova, Alisa P. Domnina, Natalia A. Pugovkina, Larisa L. Alekseenko and Irina I. Marakhova
Biomedicines 2023, 11(2), 301; https://doi.org/10.3390/biomedicines11020301 - 21 Jan 2023
Cited by 2 | Viewed by 1897
Abstract
This study describes the changes in ion homeostasis of human endometrial mesenchymal stem/stromal cells (eMSCs) during the formation of three-dimensional (3D) cell structures (spheroids) and investigates the conditions for apoptosis induction in 3D eMSCs. Detached from the monolayer culture, (2D) eMSCs accumulate Na [...] Read more.
This study describes the changes in ion homeostasis of human endometrial mesenchymal stem/stromal cells (eMSCs) during the formation of three-dimensional (3D) cell structures (spheroids) and investigates the conditions for apoptosis induction in 3D eMSCs. Detached from the monolayer culture, (2D) eMSCs accumulate Na+ and have dissipated transmembrane ion gradients, while in compact spheroids, eMSCs restore the lower Na+ content and the high K/Na ratio characteristic of functionally active cells. Organized as spheroids, eMSCs are non-proliferating cells with an active Na/K pump and a lower K+ content per g cell protein, which is typical for quiescent cells and a mean lower water content (lower hydration) in 3D eMSCs. Further, eMSCs in spheroids were used to evaluate the role of K+ depletion and cellular signaling context in the induction of apoptosis. In both 2D and 3D eMSCs, treatment with ouabain (1 µM) results in inhibition of pump-mediated K+ uptake and severe K+ depletion as well as disruption of the mitochondrial membrane potential. In 3D eMSCs (but not in 2D eMSCs), ouabain initiates apoptosis via the mitochondrial pathway. It is concluded that, when blocking the Na/K pump, cardiac glycosides prime mitochondria to apoptosis, and whether a cell enters the apoptotic pathway depends on the cell-specific signaling context, which includes the type of apoptotic protein expressed. Full article
(This article belongs to the Special Issue The Role of Na,K-ATPase in Human Health: From Structure to Function)
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18 pages, 1623 KiB  
Article
Consequences of the Lack of TNFR1 in Ouabain Response in the Hippocampus of C57BL/6J Mice
by Paula Fernanda Kinoshita, Ana Maria Orellana, Diana Zukas Andreotti, Giovanna Araujo de Souza, Natalia Prudente de Mello, Larissa de Sá Lima, Elisa Mitiko Kawamoto and Cristoforo Scavone
Biomedicines 2022, 10(11), 2937; https://doi.org/10.3390/biomedicines10112937 - 15 Nov 2022
Cited by 1 | Viewed by 2040
Abstract
Ouabain is a cardiac glycoside that has a protective effect against neuroinflammation at low doses through Na+/K+-ATPase signaling and that can activate tumor necrosis factor (TNF) in the brain. TNF plays an essential role in neuroinflammation and regulates glutamate [...] Read more.
Ouabain is a cardiac glycoside that has a protective effect against neuroinflammation at low doses through Na+/K+-ATPase signaling and that can activate tumor necrosis factor (TNF) in the brain. TNF plays an essential role in neuroinflammation and regulates glutamate receptors by acting on two different receptors (tumor necrosis factor receptor 1 [TNFR1] and TNFR2) that have distinct functions and expression. The activation of constitutively and ubiquitously expressed TNFR1 leads to the expression of pro-inflammatory cytokines. Thus, this study aimed to elucidate the effects of ouabain in a TNFR1 knockout (KO) mouse model. Interestingly, the hippocampus of TNFR1 KO mice showed a basal increase in both TNFR2 membrane expression and brain-derived neurotrophic factor (BDNF) release, suggesting a compensatory mechanism. Moreover, ouabain activated TNF-α-converting enzyme/a disintegrin and metalloprotease 17 (TACE/ADAM17), decreased N-methyl-D-aspartate (NMDA) receptor subunit 2A (NR2A) expression, and induced anxiety-like behavior in both genotype animals, independent of the presence of TNFR1. However, ouabain induced an increase in interleukin (IL)-1β in the hippocampus, a decrease in IL-6 in serum, and an increase in NMDA receptor subunit 1 (NR1) only in wild-type (WT) mice, indicating that TNFR1 or TNFR2 expression may be important for some effects of ouabain. Collectively, our results indicate a connection between ouabain signaling and TNFR1, with the effect of ouabain partially dependent on TNFR1. Full article
(This article belongs to the Special Issue The Role of Na,K-ATPase in Human Health: From Structure to Function)
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17 pages, 2972 KiB  
Article
Interaction Interface of Aβ42 with Human Na,K-ATPase Studied by MD and ITC and Inhibitor Screening by MD
by Alexei A. Adzhubei, Anna P. Tolstova, Maria A. Strelkova, Vladimir A. Mitkevich, Irina Yu. Petrushanko and Alexander A. Makarov
Biomedicines 2022, 10(7), 1663; https://doi.org/10.3390/biomedicines10071663 - 11 Jul 2022
Cited by 4 | Viewed by 1648
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease accompanied by progressive cognitive and memory dysfunction due to disruption of normal electrotonic properties of neurons and neuronal loss. The Na,K-ATPase interaction with beta amyloid (Aβ) plays an important role in AD pathogenesis. It has been [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disease accompanied by progressive cognitive and memory dysfunction due to disruption of normal electrotonic properties of neurons and neuronal loss. The Na,K-ATPase interaction with beta amyloid (Aβ) plays an important role in AD pathogenesis. It has been shown that Na,K-ATPase activity in the AD brain was significantly lower than those in age-matched control brain. The interaction of Aβ42 with Na,K-ATPase and subsequent oligomerization leads to inhibition of the enzyme activity. In this study interaction interfaces between three common Aβ42 isoforms, and different conformations of human Na,K-ATPase (α1β1) have been obtained using molecular modeling, including docking and molecular dynamics (MD). Interaction sites of Na,K-ATPase with Aβ42 are localized between extracellular parts of α- and β- subunits and are practically identical for Na,K-ATPase at different conformations. Thermodynamic parameters for the formation of Na,K-ATPase:Aβ42 complex at different conformations acquired by isothermal titration calorimetry (ITC) are similar, which is in line with the data of molecular modeling. Similarity of Na,K-ATPase interaction interfaces with Aβ in all conformations allowed us to cross-screen potential inhibitors for this interaction and find pharmaceutical compounds that could block it. Full article
(This article belongs to the Special Issue The Role of Na,K-ATPase in Human Health: From Structure to Function)
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