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

¹Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio; and ²Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas

Submitted 20 February 2007 ; accepted in final form 12 December 2007

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 ₁-polypeptide is involved in cell signaling, the role of other -isoforms (₂, ₃, and ₄) 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 ₁- and β₁-isoforms stimulated ERK phosphorylation. In contrast, expression of the ₁- and β₁-polypeptides alone resulted in no effect, indicating that the β-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 ₃β₁- and ₄β₁-isozymes, but not ₂β₁, responded to ouabain treatment. In agreement with the differences in ouabain affinity of the -polypeptides, ₁β₁ required 100- to 1,000-fold more ouabain to signal than did ₄β₁ and ₃β₁, 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.

-isoforms; Sf-9; genistein; ERK

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