Inhibition of the epithelial Na+ channel by interaction of Nedd4 with a PY motif deleted in Liddle's syndrome.

Goulet CC, Volk KA, Adams CM, Prince LS, Stokes JB, Snyder PM
J Biol Chem. 1998 273 (45): 30012-7

PMID: 9792722 · DOI:10.1074/jbc.273.45.30012

The epithelial Na+ channel (ENaC) plays a critical role in Na+ absorption in the kidney and other epithelia. Mutations in the C terminus of the beta or gammaENaC subunits increase renal Na+ absorption, causing Liddle's syndrome, an inherited form of hypertension. These mutations delete or disrupt a PY motif that was recently shown to interact with Nedd4, a ubiquitin-protein ligase expressed in epithelia. We found that Nedd4 inhibited ENaC when they were coexpressed in Xenopus oocytes. Liddle's syndrome-associated mutations that prevent the interaction between Nedd4 and ENaC abolished inhibition, suggesting that a direct interaction is required for inhibition by Nedd4. Inhibition also required activity of a ubiquitin ligase domain within the C terminus of Nedd4. Nedd4 had no detectable effect on the single channel properties of ENaC. Rather, Nedd4 decreased cell surface expression of both ENaC and a chimeric protein containing the C terminus of the beta subunit. Decreased surface expression resulted from an increase in the rate of degradation of the channel complex. Thus, interaction of Nedd4 with the C terminus of ENaC inhibits Na+ absorption, and loss of this interaction may play a role in the pathogenesis of Liddle's syndrome and other forms of hypertension.

MeSH Terms (18)

Animals Calcium-Binding Proteins Cell Membrane COS Cells Endosomal Sorting Complexes Required for Transport Epithelium Hypertension Ligases Nedd4 Ubiquitin Protein Ligases Protein Binding Rats Recombinant Fusion Proteins Sequence Deletion Sodium Channel Blockers Syndrome Ubiquitin-Protein Ligases Xenopus Xenopus Proteins

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