Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Clin Invest
1999 Mar 01;1035:667-73. doi: 10.1172/JCI5713.
Show Gene links
Show Anatomy links
Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle's syndrome.
Abriel H
,
Loffing J
,
Rebhun JF
,
Pratt JH
,
Schild L
,
Horisberger JD
,
Rotin D
,
Staub O
.
???displayArticle.abstract???
Liddle's syndrome is an inherited form of hypertension linked to mutations in the epithelial Na+ channel (ENaC). ENaC is composed of three subunits (alpha, beta, gamma), each containing a COOH-terminal PY motif (xPPxY). Mutations causing Liddle's syndrome alter or delete the PY motifs of beta- or gamma-ENaC. We recently demonstrated that the ubiquitin-protein ligase Nedd4 binds these PY motifs and that ENaC is regulated by ubiquitination. Here, we investigate, using the Xenopus oocyte system, whether Nedd4 affects ENaC function. Overexpression of wild-type Nedd4, together with ENaC, inhibited channel activity, whereas a catalytically inactive Nedd4 stimulated it, likely by acting as a competitive antagonist to endogenous Nedd4. These effects were dependant on the PY motifs, because no Nedd4-mediated changes in channel activity were observed in ENaC lacking them. The effect of Nedd4 on ENaC missing only one PY motif (of beta-ENaC), as originally described in patients with Liddle's syndrome, was intermediate. Changes were due entirely to alterations in ENaC numbers at the plasma membrane, as determined by surface binding and immunofluorescence. Our results demonstrate that Nedd4 is a negative regulator of ENaC and suggest that the loss of Nedd4 binding sites in ENaC observed in Liddle's syndrome may explain the increase in channel number at the cell surface, increased Na+ reabsorption by the distal nephron, and hence the hypertension.
Botero-Velez,
Brief report: Liddle's syndrome revisited--a disorder of sodium reabsorption in the distal tubule.
1994, Pubmed
Botero-Velez,
Brief report: Liddle's syndrome revisited--a disorder of sodium reabsorption in the distal tubule.
1994,
Pubmed
Canessa,
Epithelial sodium channel related to proteins involved in neurodegeneration.
1993,
Pubmed
,
Xenbase
Canessa,
Membrane topology of the epithelial sodium channel in intact cells.
1994,
Pubmed
,
Xenbase
Canessa,
Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.
1994,
Pubmed
,
Xenbase
Chang,
Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1.
1996,
Pubmed
Chen,
The WW domain of Yes-associated protein binds a proline-rich ligand that differs from the consensus established for Src homology 3-binding modules.
1995,
Pubmed
Dinudom,
Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+.
1998,
Pubmed
Duc,
Cell-specific expression of epithelial sodium channel alpha, beta, and gamma subunits in aldosterone-responsive epithelia from the rat: localization by in situ hybridization and immunocytochemistry.
1994,
Pubmed
Firsov,
The heterotetrameric architecture of the epithelial sodium channel (ENaC).
1998,
Pubmed
,
Xenbase
Firsov,
Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: a quantitative approach.
1996,
Pubmed
,
Xenbase
Garty,
Epithelial sodium channels: function, structure, and regulation.
1997,
Pubmed
Hansson,
Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome.
1995,
Pubmed
,
Xenbase
Hansson,
A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity.
1995,
Pubmed
,
Xenbase
Hein,
NPl1, an essential yeast gene involved in induced degradation of Gap1 and Fur4 permeases, encodes the Rsp5 ubiquitin-protein ligase.
1995,
Pubmed
Hershko,
The ubiquitin system.
1998,
Pubmed
Huibregtse,
A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase.
1995,
Pubmed
Hummler,
Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice.
1996,
Pubmed
,
Xenbase
Inoue,
A family with Liddle's syndrome caused by a new missense mutation in the beta subunit of the epithelial sodium channel.
1998,
Pubmed
,
Xenbase
Ishikawa,
Electrophysiological characterization of the rat epithelial Na+ channel (rENaC) expressed in MDCK cells. Effects of Na+ and Ca2+.
1998,
Pubmed
Kellenberger,
Mutations causing Liddle syndrome reduce sodium-dependent downregulation of the epithelial sodium channel in the Xenopus oocyte expression system.
1998,
Pubmed
,
Xenbase
Kumar,
Identification of a set of genes with developmentally down-regulated expression in the mouse brain.
1992,
Pubmed
Lingueglia,
Different homologous subunits of the amiloride-sensitive Na+ channel are differently regulated by aldosterone.
1994,
Pubmed
,
Xenbase
Lingueglia,
Expression cloning of an epithelial amiloride-sensitive Na+ channel. A new channel type with homologies to Caenorhabditis elegans degenerins.
1993,
Pubmed
,
Xenbase
Lingueglia,
Cloning of the amiloride-sensitive FMRFamide peptide-gated sodium channel.
1995,
Pubmed
,
Xenbase
Mastroberardino,
Ras pathway activates epithelial Na+ channel and decreases its surface expression in Xenopus oocytes.
1998,
Pubmed
,
Xenbase
O'Brodovich,
The role of active Na+ transport by lung epithelium in the clearance of airspace fluid.
1995,
Pubmed
Rebhun,
Molecular cloning of Nedd4 from Xenopus laevis.
1998,
Pubmed
,
Xenbase
Renard,
Biochemical analysis of the membrane topology of the amiloride-sensitive Na+ channel.
1994,
Pubmed
,
Xenbase
Scheffner,
Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade.
1995,
Pubmed
Schild,
A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system.
1995,
Pubmed
,
Xenbase
Schild,
Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome.
1996,
Pubmed
,
Xenbase
Shimkets,
Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel.
1994,
Pubmed
Shimkets,
The activity of the epithelial sodium channel is regulated by clathrin-mediated endocytosis.
1997,
Pubmed
,
Xenbase
Snyder,
Membrane topology of the amiloride-sensitive epithelial sodium channel.
1994,
Pubmed
,
Xenbase
Snyder,
Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel.
1995,
Pubmed
,
Xenbase
Staub,
WW domains.
1996,
Pubmed
Staub,
Immunolocalization of the ubiquitin-protein ligase Nedd4 in tissues expressing the epithelial Na+ channel (ENaC).
1997,
Pubmed
Staub,
Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination.
1997,
Pubmed
,
Xenbase
Staub,
WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome.
1996,
Pubmed
Stutts,
CFTR as a cAMP-dependent regulator of sodium channels.
1995,
Pubmed
Tamura,
Liddle disease caused by a missense mutation of beta subunit of the epithelial sodium channel gene.
1996,
Pubmed
,
Xenbase
