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Am J Physiol Renal Physiol (December 19, 2007). doi:10.1152/ajprenal.00089.2007
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Submitted on February 20, 2007
Accepted on December 12, 2007

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

Sandrine V Pierre1*, Yoann Sottejeau1, Jean-Michel Gourbeau1, Gladis Sanchez2, Amjad Shidyak3, and V. Gustavo Blanco4

1 Department of Physiology, Pharmacology, Metabolism and Cardiovascular Sciences, University of Toledo College of Medicine, Toledo, Ohio, United States
2 Department of Molecular and Integrative Physiology, Univ Kansas Med Ctr, Kansas City, Kansas, United States
3 Department of Medicine, University of Toledo College of Medicine, Toledo, Ohio, United States
4 Univ Kansas Med Ctr, United States

* To whom correspondence should be addressed. E-mail: sandrine.pierre{at}utoledo.edu.

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 {alpha}1 polypeptide is involved in cell signaling, the role of other {alpha}isoforms ({alpha}2, {alpha}3 and {alpha}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 co-expressing Na,K-ATPase {alpha}1 and {beta}1 isoforms stimulated ERK phosphorylation. In contrast, expression of the {alpha}1 and{beta}1 polypeptides alone resulted in no effect, indicating that the {alpha}{beta} complex is necessary for Na,K-ATPase signaling. Moreover, 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 {alpha}3{beta}1 and {alpha}4{beta}1 isozymes, but not {alpha}2{beta}1 responded to ouabain treatment. In agreement with the differences in ouabain affinity of the {alpha} polypeptides, {alpha}1{beta}1 required 100 to 1000 fold more ouabain to signal than {alpha}4{beta}1 and {alpha}3{beta}1, 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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