Ouabain as a Mammalian Hormone

Schoner, Wilhelm; Bauer, Natali; Müller‐Ehmsen, Jochen; Krämer, Ulrike M.; Hambarchian, Njde; Schwinger, Robert H. G.; Moêller, H.; Kost, Holger; Weitkamp, Christine; Schweitzer, Thomas; Kirch, Ulrike; Neu, Horst; Grünbaum, Ernst-Güngther

doi:10.1111/j.1749-6632.2003.tb07282.x

Cited by 52 publications

(43 citation statements)

References 22 publications

(24 reference statements)

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“…The present demonstration that ouabain affects cell-cell interaction by enhancing the expression of connexin 32 and suppressing the P3A mechanism indicates that one of the physiological roles of this hormone is to determine the fate of a cell through cell adhesion. These results may afford clues to why ouabain plays an important role in health and disease (3,4,28).…”

Section: Discussionmentioning

confidence: 92%

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Contacts and cooperation between cells depend on the hormone ouabain

Larre

Ponce

Fiorentino

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cell adhesion is a crucial step in proliferation, differentiation, migration, apoptosis, and metastasis. In previous works we have shown that cell adhesion is modulated by ouabain, a highly specific inhibitor of Na ؉ ,K ؉ -ATPase, recently found to be a hormone. In the present work we pursue the investigation of the effect of ouabain on a special type of cell-cell interaction: the rescue of ouabainsensitive MDCK cells (W) by ouabain-resistant cells (R). In cultured monolayers of pure W cells, ouabain triggers the ''P3 A mechanism'' (from pump͞adhesion) consisting of a cascade of phosphorylations that retrieves adhesion-associated molecules occludin and ␤-catenin and results in detachment of the cell. When W cells are instead cocultured with R cells, the P3 A reaction is blocked, and W cells are rescued. Furthermore, in these R͞W cocultures ouabain promotes cell-cell communication by means of gap junctions by specifically enhancing the expression of connexin 32 and addressing this molecule to the plasma membrane. Ouabain also promotes the internalization of the ␤-subunit of the Na ؉ ,K ؉ -ATPase. These observations open the possibility that the crucial processes mentioned at the beginning would be under the control of the hormone ouabain.ardiotonic steroids started in the 18th century as unknown active principles when William Withering used foxglove tea (Digitalis purpurea) to treat dropsy (congestive heart failure). Once ouabain was isolated, the demonstration that it specifically inhibits the Na ϩ ,K ϩ pump (1) transformed ouabain into a crucial tool to identify the pump with the membrane enzyme Na ϩ ,K ϩ -ATPase (2) and unravel its intrinsic mechanisms. Ouabain was recently recognized to be a hormone (3) whose blood level increases in physiological (e.g., exercise) as well as pathological (e.g., arterial hypertension, chronic cardiac and renal failure, preeclampsia, etc.) conditions (4-7). Furthermore, we found that ouabain specifically decreases cell adhesion by triggering a P3A mechanism that involves the activation of protein tyrosine kinases and extracellular signal-regulated kinases, decreases the cell content of the small GTP-binding protein RhoA, and changes the degree of phosphorylation, internalization, and degradation of adhesion molecules such as occludin, E-cadherin, etc. (8, 9) (D. Flores-Benítez, personal communication). We have also shown that detachment may not be ascribed to the ensuing decrease of K content (8) and that a decrease of K content provoked by incubation of R or W cells in media with only 0.1 mM K ϩ (instead of the regular 4.0 mM) does not cause cell detachment (8). This finding is in keeping with the fact that changes in reduced͞oxidized glutathione modify the degree of ouabain resistance without reducing the cell K (10, 11).Because in the meanwhile ouabain was shown to be a hormone (3), in the present work we pursue the study of its effect on a special type of cell-cell interaction: metabolic cooperation (12). A typical example of cooperation is provided by R cells that have low...

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Section: Discussionmentioning

confidence: 92%

“…Because in the meanwhile ouabain was shown to be a hormone (3), in the present work we pursue the study of its effect on a special type of cell-cell interaction: metabolic cooperation (12). A typical example of cooperation is provided by R cells that have low affinity for ouabain (13,14) and rescue neighboring cells whose pumps have been blocked (15).…”

mentioning

confidence: 99%

Contacts and cooperation between cells depend on the hormone ouabain

Larre

Ponce

Fiorentino

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Exercise and stress cause an acute rise in EO circulating levels (55). EO release from the adrenal cortical cells is stimulated by angiotensin II and catecholamines.…”

Section: Discussionmentioning

confidence: 99%

Cardiotonic Steroids Stimulate Glycogen Synthesis in Human Skeletal Muscle Cells via a Src- and ERK1/2-dependent Mechanism

Kotova

Al-Khalili

Talia

et al. 2006

Journal of Biological Chemistry

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The cardiotonic steroid, ouabain, a specific inhibitor of Na ؉ ,K ؉ -ATPase, initiates protein-protein interactions that lead to an increase in growth and proliferation in different cell types. We explored the effects of ouabain on glucose metabolism in human skeletal muscle cells (HSMC) and clarified the mechanisms of ouabain signal transduction. In HSMC, ouabain increased glycogen synthesis in a concentration-dependent manner reaching the maximum at 100 nM. The effect of ouabain was additive to the effect of insulin and was independent of phosphatidylinositol 3-kinase inhibitor LY294002 but was abolished in the presence of a MEK1/2 inhibitor (PD98059) or a Src inhibitor (PP2). Ouabain increased Src-dependent tyrosine phosphorylation of ␣ 1 -and ␣ 2 -subunits of Na ؉ ,K ؉ -ATPase and promoted interaction of ␣ 1 -and ␣ 2 -subunits with Src, as assessed by co-immunoprecipitation with Src. Phosphorylation of ERK1/2 and GSK3␣/␤, as well as p90rsk activity, was increased in response to ouabain in HSMC, and these responses were prevented in the presence of PD98059 and PP2. Incubation of HSMC with 100 nM ouabain increased phosphorylation of the ␣-subunits of the Na-pump at a MAPK-specific Thr-Pro motif. Ouabain treatment decreased the surface abundance of ␣ 2 -subunit, whereas abundance of the ␣ 1 -subunit was unchanged. Marinobufagenin, an endogenous vertebrate bufadienolide cardiotonic steroid, increased glycogen synthesis in HSMC at 10 nM concentration, similarly to 100 nM ouabain. In conclusion, ouabain and marinobufagenin stimulate glycogen synthesis in skeletal muscle. This effect is mediated by activation of a Src-, ERK1/2-, p90rsk-, and GSK3-dependent signaling pathway.

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“…This particular functional property appears to be physiologically important in regulating Na-K-ATPase activity in an isoform-specific manner (3,12). In support of the biological importance of a modulatory action for ouabain, the cardiotonic steroid has been found to exist as an endogenous substance that circulates in plasma of humans and other mammals (10,25). In addition to regulating enzymatic and transport activities, the differences in affinity of Na-K-ATPase isoforms for ouabain may translate into differences in the ability of each ␣-polypeptide to relay ouabain-binding signals into the cell.…”

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confidence: 99%

Isoform specificity of Na-K-ATPase-mediated ouabain signaling

Pierre

Sottejeau²,

Gourbeau³

et al. 2008

American Journal of Physiology-Renal Physiology

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The ion transporter Na-K-ATPase functions as a cell signal transducer that mediates ouabain-induced activation of protein kinases, such as ERK. While Na-K-ATPase composed of the α1-polypeptide is involved in cell signaling, the role of other α-isoforms (α2, α3, and α4) in transmitting ouabain effects is unknown. We have explored this using baculovirus-directed expression of Na-K-ATPase polypeptides in insect cells and ERK phosphorylation as an indicator of ouabain-induced signaling. Ouabain addition to Sf-9 cells coexpressing Na-K-ATPase α1- and β1-isoforms stimulated ERK phosphorylation. In contrast, expression of the α1- and β1-polypeptides alone resulted in no effect, indicating that the αβ-complex is necessary for Na-K-ATPase signaling. Moreover, the ouabain effect was sensitive to genistein, suggesting that Na-K-ATPase-mediated tyrosine kinase activation is a critical event in the intracellular cascade leading to ERK phosphorylation. In addition, the Na-K-ATPases α3β1- and α4β1-isozymes, but not α2β1, responded to ouabain treatment. In agreement with the differences in ouabain affinity of the α-polypeptides, α1β1 required 100- to 1,000-fold more ouabain to signal than did α4β1 and α3β1, respectively. These results confirm the role of the Na-K-ATPase in ouabain signal transduction, show that there are important isoform-specific differences in Na-K-ATPase signaling, and demonstrate the suitability of the baculovirus expression system for studying Na-K-ATPase-mediated ouabain effects.

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Ouabain as a Mammalian Hormone

Cited by 52 publications

References 22 publications

Contacts and cooperation between cells depend on the hormone ouabain

Contacts and cooperation between cells depend on the hormone ouabain

Cardiotonic Steroids Stimulate Glycogen Synthesis in Human Skeletal Muscle Cells via a Src- and ERK1/2-dependent Mechanism

Isoform specificity of Na-K-ATPase-mediated ouabain signaling

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