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J. Biol. Chem., Vol. 281, Issue 20, 14129-14135, May 19, 2006

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Clathrin-mediated Endocytosis of the Epithelial Sodium Channel

ROLE OF EPSIN^*

Huamin Wang, Linton M. Traub, Kelly M. Weixel, Mathew J. Hawryluk, Nirav Shah, Robert S. Edinger, Clint J. Perry, Lauren Kester, Michael B. Butterworth, Kathryn W. Peters, Thomas R. Kleyman, Raymond A. Frizzell, and John P. Johnson¹

From the Renal-Electrolyte Division, Departments of Medicine and Physiology and Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Here we present evidence that the epithelial sodium channel (ENaC), a heteromeric membrane protein whose surface expression is regulated by ubiquitination, is present in clathrin-coated vesicles in epithelial cells that natively express ENaC. The channel subunits are ubiquitinated and co-immunoprecipitate with both epsin and clathrin adaptor proteins, and epsin, as expected, co-immunoprecipitates with clathrin adaptor proteins. The functional significance of these interactions was evaluated in a Xenopus oocyte expression system where co-expression of epsin and ENaC resulted in a down-regulation of ENaC activity; conversely, co-expression of epsin sub-domains acted as dominant-negative effectors and stimulated ENaC activity. These results identify epsin as an accessory protein linking ENaC to the clathrin-based endocytic machinery thereby regulating the activity of this ion channel at the cell surface.

Received for publication, November 22, 2005 , and in revised form, March 23, 2006.

^* This work was supported by National Institutes of Health Grants DK 57718 (to J. P. J.), DK65161 (to T. R. K.), DK 54814 (to R. A. F.), and DK 53249 (to L. M. T.). 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 To whom correspondence should be addressed: 935 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261. Tel.: 412-647-7157; Fax: 412-647-6222; E-mail: johnson{at}dom.pitt.edu.

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