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This Article Full Text Full Text (PDF) All Versions of this Article: 295/2/F426    most recent 00516.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Khundmiri, S. J. Articles by Lederer, E. D. Search for Related Content PubMed PubMed Citation Articles by Khundmiri, S. J. Articles by Lederer, E. D.

PTH-mediated regulation of Na⁺-K⁺-ATPase requires Src kinase-dependent ERK phosphorylation

¹Department of Medicine, University of Louisville, Louisville, Kentucky; ²Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona; and ³Veterans Affairs Medical Center, Louisville, Kentucky

Submitted 5 November 2007 ; accepted in final form 4 June 2008

Parathyroid hormone (PTH) inhibits Na⁺-K⁺-ATPase activity by serine phosphorylation of the ₁-subunit through ERK-dependent phosphorylation and translocation of protein kinase C (PKC). On the basis of previous studies, we postulated that PTH regulates sodium pump activity through Src kinase, PLC, and calcium-dependent ERK phosphorylation. In the present work utilizing opossum kidney cells, a model of renal proximal tubule, PTH-stimulated ERK phosphorylation and membrane translocation of PKC were prevented by inhibition of Src kinase, PLC, and calcium entry. Pharmacological inhibition of PLA₂ did not prevent PTH-stimulated ERK phosphorylation but completely prevented PKC translocation. Silencing the expression of cytosolic or calcium-independent PLA₂ also prevented PTH-mediated phosphorylation of Na⁺-K⁺-ATPase ₁-subunit and PKC without blocking ERK phosphorylation. Inhibition of Na⁺-K⁺-ATPase activity by the PLA₂ metabolites arachidonic acid and 20-hydroxyeicosatetraenoic acid was prevented by specific inhibition of PKC but not by U0126, a MEK-1 inhibitor. Transient transfection of constitutively active MEK-1 cDNA induced phosphorylation of Na⁺-K⁺-ATPase ₁-subunit and PKC, which was prevented by PLA₂ inhibition. We conclude that PTH stimulates Na⁺-K⁺-ATPase phosphorylation and decreases the activity of Na⁺-K⁺-ATPase by a sequential activation of a signaling pathway involving Src kinase, PLC, ERK, PLA₂, and PKC.

Na⁺-K⁺-ATPase ₁-subunit; parathyroid hormone; phospholipase C; extracellular signal-regulated kinase; phospholipase A₂; protein kinase C

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