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J. Biol. Chem., Vol. 281, Issue 36, 26159-26169, September 8, 2006

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AMP-activated Kinase Inhibits the Epithelial Na⁺ Channel through Functional Regulation of the Ubiquitin Ligase Nedd4-2^*

Vivek Bhalla, Nicholas M. Oyster, Adam C. Fitch, Marjolein A. Wijngaarden, Dietbert Neumann^¶, Uwe Schlattner^¶, David Pearce, and Kenneth R. Hallows¹

From the Division of Nephrology, Department of Medicine, University of California at San Francisco, San Francisco, California 94107, the Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, and the ^¶Institute of Cell Biology, ETH Zurich, 8093 Zurich, Switzerland

We recently found that the metabolic sensor AMP-activated kinase (AMPK) inhibits the epithelial Na⁺ channel (ENaC) through decreased plasma membrane ENaC expression, an effect requiring the presence of a binding motif in the cytoplasmic tail of the -ENaC subunit for the ubiquitin ligase Nedd4-2. To further examine the role of Nedd4-2 in the regulation of ENaC by AMPK, we studied the effects of AMPK activation on ENaC currents in Xenopus oocytes co-expressing ENaC and wild-type (WT) or mutant forms of Nedd4-2. ENaC inhibition by AMPK was preserved in oocytes expressing WT Nedd4-2 but blocked in oocytes expressing either a dominant-negative (DN) or constitutively active (CA) Nedd4-2 mutant, suggesting that AMPK-dependent modulation of Nedd4-2 function is involved. Similar experiments utilizing WT or mutant forms of the serum- and glucocorticoid-regulated kinase (SGK1), modulators of protein kinase A (PKA), or extracellular-regulated kinase (ERK) did not affect ENaC inhibition by AMPK, suggesting that these pathways known to modulate the Nedd4-2-ENaC interaction are not responsible. AMPK-dependent phosphorylation of Nedd4-2 expressed in HEK-293 cells occurred both in vitro and in vivo, suggesting a potential mechanism for modulation of Nedd4-2 and thus cellular ENaC activity. Moreover, cellular AMPK activation significantly enhanced the interaction of the -ENaC subunit with Nedd4-2, as measured by co-immunoprecipitation assays in HEK-293 cells. In summary, these results suggest a novel mechanism for ENaC regulation in which AMPK promotes ENaC-Nedd4-2 interaction, thereby inhibiting ENaC by increasing Nedd4-2-dependent ENaC retrieval from the plasma membrane. AMPK-dependent ENaC inhibition may limit cellular Na⁺ loading under conditions of metabolic stress when AMPK becomes activated.

Received for publication, June 23, 2006 , and in revised form, July 12, 2006.

^* This work was supported in part by National Institutes of Health Grants K08 DK071648 (to V. B.), R01 DK056695 (to D. P.), and K08 DK059477 and R03 DK068390 (to K. R. H.), the Cystic Fibrosis Foundation (HALLOW06P0, to K. R. H.), and Swiss Natl. Science Foundation Grant No. 3100A0-102075 (to U. S.). 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.

¹ A Carl W. Gottschalk Research Scholar of the American Society of Nephrology. To whom correspondence should be addressed: Renal-Electrolyte Division, Dept. of Medicine, University of Pittsburgh School of Medicine, S976 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261. Tel.: 412-648-9580; Fax: 412-383-8956; E-mail: hallows{at}pitt.edu.

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