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INVITED REVIEW

Regulation of epithelial sodium channels by the ubiquitin-proteasome proteolytic pathway

¹Department of Physiology and ²Renal Division, Emory University, Atlanta, Georgia; and ³Department of Nephrology, Baylor College of Medicine, Houston, Texas

Amiloride-sensitive epithelial Na⁺ channels (ENaC) play a crucial role in Na⁺ transport and fluid reabsorption in the kidney, lung, and colon. The magnitude of ENaC-mediated Na⁺ transport in epithelial cells depends on the average open probability of the channels and the number of channels on the apical surface of epithelial cells. The number of channels in the apical membrane, in turn, depends on a balance between the rate of ENaC insertion and the rate of removal from the apical membrane. ENaC is made up of three homologous subunits: , , and . The COOH-terminal domain of all three subunits is intracellular and contains a proline-rich motif (PPxY). Mutations or deletion of this PPxY motif in the - and -subunits prevent the binding of one isoform of a specific ubiquitin ligase, neural precursor cell-expressed, developmentally downregulated protein (Nedd4–2), to the channel in vitro and in transfected cell systems, thereby impeding ubiquitin conjugation of the channel subunits. Ubiquitin conjugation would seem to imply that ENaC turnover is determined by the ubiquitin-proteasome system, but when Madin-Darby canine kidney cells are transfected with ENaC, ubiquitin conjugation apparently leads to lysosomal degradation. However, in untransfected renal cells (A6) expressing endogenous ENaC, ENaC is indeed degraded by the ubiquitin-proteasome system. Nonetheless, in both transfected and untransfected cells, the rate of ENaC degradation is apparently controlled by Nedd4–2 activity. In this review, we discuss the role of the ubiquitin conjugation and the alternative degradative pathways (lysosomal or proteasomal) in regulating the rate of ENaC turnover in untransfected renal cells and compare this regulation to that of transfected cell systems.

Nedd4; Sgk; A6 cells; amiloride sensitive; membrane-spanning protein

This article has been cited by other articles:

				N. S. Raikwar and C. P. Thomas Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1157 - F1165. [Abstract] [Full Text] [PDF]