Na<sup>+</sup>-K<sup>+</sup>-ATPase, a new class of plasma membrane receptors

Aperia, Anita; Akkuratov, Evgeny E.; Fontana, Jacopo Maria; Brismar, Hjalmar

doi:10.1152/ajpcell.00359.2015

Cited by 94 publications

(82 citation statements)

References 74 publications

(78 reference statements)

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“…As we have shown, challenging MDCK cells with 10 nM, a concentration within its physiological range triggers a series of changes in the epithelial phenotype, which includes tight junctions, ciliogenesis and gap junctional communication. The effects of hormone ouabain start with the binding of ouabain to the α-subunit of Na + /K + -ATPase, that acts as a receptor [14,15], which in turn, activates a signaling pathway involving c-Src and ERK1/2 [50]. This indicates that the same signaling route mediates all the hormonal effects on cell contacts so far tested.…”

Section: Discussionmentioning

confidence: 99%

“…Recently it has been found that Na+/K+-ATPase also acts as a receptor of ouabain [11,12]. Binding of ouabain to Na+/K+-ATPase unleash a cascade of interrelated signal transduction pathways that involves inositol (3, 4, 5)-tris-phosphate receptor, Src kinase, tyrosine phosphorylation, epidermal growth factor receptor, Ras and the Ras/Raf/MEK/MAPK signaling pathway [13][14][15]. Following this scheme, ouabain has shown to influence a wide variety of physiological processes, including proliferation [16,17], growth [18], apoptosis [19][20][21] and cell mobility [22] in different tissues and organs.…”

Section: Introductionmentioning

confidence: 99%

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Ouabain Modulates the Distribution of Connexin 43 in Epithelial Cells

Ponce

Larre

Castillo

et al. 2016

Cell Physiol Biochem

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Background/Aims: The fact that ouabain has been identified as an endogenous substance, led us to inquire its physiological role in epithelial cells. Based on previous observations, we hypothesized that it influences processes related to cell contacts. Previously we have shown that nanomolar concentrations of ouabain up-regulate tight junctions, accelerate ciliogenesis, and increase gap junctional intercellular communication (GJIC). Given that silencing assays indicated that connexin 43 (Cnx43) is involved in the GJIC response, in the present work we study whether ouabain affects Cnx43 expression and distribution. Methods: We seeded confluent monolayers of epithelial renal MDCK cells and incubated them with 10 nM ouabain during 1 h. Then we measured, by densitometric analysis of Western blot assays, the amount of Cnx43 in cells and in fractions enriched of plasma membrane. We also studied its localization with immunofluorescence and confocal microscopy. Results: Cnx43 is remarkably displayed, outlining the borders of cells gathered in clusters, randomly scattered throughout the monolayer. Ouabain increases the density of such clusters, as well as the average number of cells per cluster, without inducing the synthesis of new Cnx43. It also promotes relocation towards the membrane, of subunits already available. The fact that such changes are inhibited by PP2 and PD98059 indicates that a signaling pathway, that includes c-Src and ERK1/2, is involved in this response. Conclusion: Ouabain induces the translocation of Cnx43 from the cytoplasm to the plasma membrane. These findings support our hypothesis that one of the physiological roles of ouabain is the modulation of physiological processes that depend on cell to cell contacts.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ouabain Modulates the Distribution of Connexin 43 in Epithelial Cells

Ponce

Larre

Castillo

et al. 2016

Cell Physiol Biochem

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“…In the body, cardiotonic steroids may arise from medication, but low levels of endogenous cardiotonic steroids have also been measured (Aperia et al, 2016). It remains controversial what the physiological significance of Na,K-ATPase signaling may be, and transcriptome differences in response to cardiotonic steroids were only seen if the relative intracellular concentrations of sodium and potassium changed, i.e., if there was a direct effect on the ion pumping mechanism (Klimanova et al, 2017).…”

Section: Cardiotonic Steroidsmentioning

confidence: 99%

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

2017

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The sodium and potassium gradients across the plasma membrane are used by animal cells for numerous processes, and the range of demands requires that the responsible ion pump, the Na,K-ATPase, can be fine-tuned to the different cellular needs. Therefore, several isoforms are expressed of each of the three subunits that make a Na,K-ATPase, the alpha, beta and FXYD subunits. This review summarizes the various roles and expression patterns of the Na,K-ATPase subunit isoforms and maps the sequence variations to compare the differences structurally. Mutations in the Na,K-ATPase genes encoding alpha subunit isoforms have severe physiological consequences, causing very distinct, often neurological diseases. The differences in the pathophysiological effects of mutations further underline how the kinetic parameters, regulation and proteomic interactions of the Na,K-ATPase isoforms are optimized for the individual cellular needs.

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“…Na,K-ATPase is a major gradient-forming enzyme moving Na + and K + against their electrochemical gradients. In addition Na,K-ATPase is a receptor for cardiotonic steroids and a mediator of complex signaling cascades involving kinases, Ca 2+ , and mitochondrial free radical burst [1], [55]. Whereas lower doses of cardiotonic steroids evoke signaling response of the Na,K-ATPase, at higher concentrations these compounds inhibit transport function of the enzyme [56].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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 O2-sensitivity of Na,K-ATPase signaling function. Moreover, modeling predicted that S-glutathionylation of Cys 458 and 459 should prevent inhibitory binding of Src to NBD. Our data indicate for the first time that cysteine residues within the AD and NBD influence hydrolytic as well as receptor function of the Na,K-ATPase and alter responses of the enzyme to hypoxia or upon treatment with cardiotonic steroids.

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Na⁺-K⁺-ATPase, a new class of plasma membrane receptors

Cited by 94 publications

References 74 publications

Ouabain Modulates the Distribution of Connexin 43 in Epithelial Cells

Ouabain Modulates the Distribution of Connexin 43 in Epithelial Cells

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

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

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Na+-K+-ATPase, a new class of plasma membrane receptors

Cited by 94 publications

References 74 publications

Ouabain Modulates the Distribution of Connexin 43 in Epithelial Cells

Ouabain Modulates the Distribution of Connexin 43 in Epithelial Cells

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

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

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Na⁺-K⁺-ATPase, a new class of plasma membrane receptors