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Minireview: Regulation of Epithelial Na⁺ Channel Trafficking

Departments of Internal Medicine and Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa 52242

Address all correspondence and requests for reprints to: Peter M. Snyder, 371 E.M.R.B., University of Iowa, Iowa City, Iowa 52242. E-mail: peter-snyder{at}uiowa.edu.

The epithelial Na⁺ channel (ENaC) is a pathway for Na⁺ transport across epithelia, including the kidney collecting duct, lung, and distal colon. ENaC is critical for Na⁺ homeostasis and blood pressure control; defects in ENaC function and regulation are responsible for inherited forms of hypertension and hypotension and may contribute to the pathogenesis of cystic fibrosis and other lung diseases. An emerging theme is that epithelial Na⁺ transport is regulated in large part through trafficking mechanisms that control ENaC expression at the cell surface. ENaC trafficking is regulated at multiple steps. Delivery of channels to the cell surface is regulated by aldosterone (and corticosteroids) and vasopressin, which increase ENaC synthesis and exocytosis, respectively. Conversely, endocytosis and degradation is controlled by a sequence located in the C terminus of , ß, and ENaC (PPPXYXXL). This sequence functions as an endocytosis motif and as a binding site for Nedd4-2, an E3 ubiquitin protein ligase that targets ENaC for degradation. Mutations that delete or disrupt this motif cause accumulation of channels at the cell surface, resulting in Liddle’s syndrome, an inherited form of hypertension. Nedd4-2 is a central convergence point for ENaC regulation by aldosterone and vasopressin; both induce phosphorylation of a common set of three Nedd4-2 residues, which blocks Nedd4-2 binding to ENaC. Thus, aldosterone and vasopressin regulate epithelial Na⁺ transport in part by altering ENaC trafficking to and from the cell surface.

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