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J. Biol. Chem., Vol. 280, Issue 10, 8705-8713, March 11, 2005

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Parathyroid Hormone-mediated Regulation of Na⁺-K⁺-ATPase Requires ERK-dependent Translocation of Protein Kinase C^*

Syed J. Khundmiri, William L. Dean¶, Kenneth R. McLeish¶||, and Eleanor D. Lederer||

From the Departments of Medicine and ^¶Biochemistry and Molecular Biology, University of Louisville and ^||Veterans Affairs Medical Center, Louisville, Kentucky 40202

Parathyroid hormone (PTH) inhibits Na⁺-K⁺-ATPase activity by serine phosphorylation of the ₁ subunit through protein kinase C (PKC)- and extracellular signal-regulated kinase (ERK)-dependent pathways. Based on previous studies we postulated that PTH regulates sodium pump activity through isoform-specific PKC-dependent activation of ERK. In the present work utilizing opossum kidney cells, a model of renal proximal tubule, PTH stimulated membrane translocation of PKC by 102 ± 16% and PKCI by 41 ± 7% but had no effect on PKCII and PKC. Both PKC and PKCI phosphorylated the Na⁺-K⁺-ATPase ₁ subunit in vitro. PTH increased the activity of PKC but not PKCI. Coimmunoprecipitation assays demonstrated that treatment with PTH enhanced the association between Na⁺-K⁺-ATPase ₁ subunit and PKC, whereas the association between Na⁺-K⁺-ATPase ₁ subunit and PKCI remained unchanged. A PKC inhibitory peptide blocked PTH-stimulated serine phosphorylation of the Na⁺-K⁺-ATPase ₁ subunit and inhibition of Na⁺-K⁺-ATPase activity. Pharmacologic inhibition of MEK-1 blocked PTH-stimulated translocation of PKC, whereas transfection of constitutively active MEK-1 cDNA induced translocation of PKC and increased phosphorylation of the Na⁺-K⁺-ATPase ₁ subunit. In contrast, PTH-stimulated ERK activation was not inhibited by pretreatment with the PKC inhibitory peptide. Inhibition of PKC expression by siRNA did not inhibit PTH-mediated ERK activation but significantly reduced PTH-mediated phosphorylation of the Na⁺-K⁺-ATPase ₁ subunit. Pharmacologic inhibition of phosphoinositide 3-kinase blocked PTH-stimulated ERK activation, translocation of PKC, and phosphorylation of the Na⁺-K⁺-ATPase ₁ subunit. We conclude that PTH stimulates Na⁺-K⁺-ATPase phosphorylation and decreases the activity of Na⁺-K⁺-ATPase by ERK-dependent activation of PKC.

Received for publication, July 29, 2004 , and in revised form, December 14, 2004.

^* This work was supported by Veterans Affairs Merit Reviews (to E. D. L. and K. R. M.); Scientist Development Grant 0435153N from the American Heart Association; American Heart Association, Ohio Valley Affiliate, Postdoctoral Fellowship Grant 0120318B (to S. J. K.); NIDDK, National Institutes of Health Grant DK62389 (to K. R. M.); and American Heart Association, Ohio Valley Affiliate, Grant-in-aid 0355350 (to W. L. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Kidney Disease Program, University of Louisville, 570 S Preston St., Louisville, KY 40202. Tel.: 502-852-0014; Fax: 502-852-4384; E-mail: syed.khundmiri{at}louisville.edu.

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