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Originally published In Press as doi:10.1074/jbc.M010626200 on January 26, 2001

J. Biol. Chem., Vol. 276, Issue 16, 12903-12910, April 20, 2001
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ENaC Degradation in A6 Cells by the Ubiquitin-Proteosome Proteolytic Pathway*

Bela MalikDagger , Lynn Schlanger§, Otor Al-KhaliliDagger , Hui-Fang BaoDagger , Guichun YueDagger , Stephen Russ Price§, William E. Mitch§, and Douglas Charles EatonDagger

From the Dagger  Department of Physiology and § Renal Division, Emory University, Atlanta, Georgia 30322

Amiloride-sensitive epithelial Na+ channels (ENaC) are responsible for trans-epithelial Na+ transport in the kidney, lung, and colon. The channel consists of three subunits (alpha , beta , gamma ) each containing a proline rich region (PPXY) in their carboxyl-terminal end. Mutations in this PPXY domain cause Liddle's syndrome, an autosomal dominant, salt-sensitive hypertension, by preventing the channel's interactions with the ubiquitin ligase Neural precursor cell-expressed developmentally down-regulated protein (Nedd4). It is postulated that this results in defective endocytosis and lysosomal degradation of ENaC leading to an increase in ENaC activity. To show the pathway that degrades ENaC in epithelial cells that express functioning ENaC channels, we used inhibitors of the proteosome and measured sodium channel activity. We found that the inhibitor, MG-132, increases amiloride-sensitive trans-epithelial current in Xenopus distal nephron A6 cells. There also is an increase of total cellular as well as membrane-associated ENaC subunit molecules by Western blotting. MG-132-treated cells also have increased channel density in patch clamp experiments. Inhibitors of lysosomal function did not reproduce these findings. Our results suggest that in native renal cells the proteosomal pathway is an important regulator of ENaC function.

* This work was supported by National Institutes of Health Grants DK-37963-14 and DK-50268-4 (to D. C. E.), Grant DK-37175 (to W. E. M.), and DK-50740 (to S. R. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The 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: Dept. of Physiology, Center for Cell and Molecular Signaling, Physiology Bldg., Rm. 074, 1648 Pierce Dr., Atlanta, GA 30322. Tel.:404-727-7247; Fax: 404- 727-0029; E-mail: bmalik@ccms-renal.physio.emory.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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