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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/F1157    most recent 00339.2007v1 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 PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Raikwar, N. S. Articles by Thomas, C. P. PubMed PubMed Citation Articles by Raikwar, N. S. Articles by Thomas, C. P.

Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel

¹Department of Internal Medicine, ²Graduate Program in Molecular Biology, University of Iowa College of Medicine and ³Veterans Affairs Medical Center, Iowa City, Iowa

Submitted 19 July 2007 ; accepted in final form 3 March 2008

We previously reported the existence of multiple isoforms of human Nedd4-2 (Am J Physiol Renal Physiol 285: F916–F929, 2003). When overexpressed in M-1 collecting duct epithelia, full-length Nedd4-2 (Nedd4-2), Nedd4-2 lacking the NH₂-terminal C2 domain (Nedd4-2C2), and Nedd4-2 lacking WW domains 2 and 3 (Nedd4-2WW2,3) variably reduce benzamil-sensitive Na⁺ transport. We investigated the effect of each of the Nedd4-2 isoforms on cell surface expression and ubiquitination of ENaC subunits. We find that ENaC when transfected alone or with β and ENaC is expressed at the cell surface and this membrane expression is variably reduced by coexpression with each of the Nedd4-2 isoforms. Nedd4-2 reduces the half-life of ENaC subunits and enhances the ubiquitination of , β, and ENaC subunits when expressed alone or together suggesting that each subunit is a target for Nedd4-2-mediated ubiquitination. As has been reported recently, we confirm that the surface-expressed pool of ENaC is multi-ubiquitinated. Inhibitors of the proteasome increase ubiquitination of ENaC subunits and stimulate Na⁺ transport in M-1 cells consistent with a role for the ubiquitin-proteasome pathway in regulating Na⁺ transport in the collecting duct.

sodium transport; collecting duct; hypertension