Regulation of the epithelial Na+ channel by Nedd4 and ubiquitination.

Détails

ID Serval
serval:BIB_0CA7515100EF
Type
Article: article d'un périodique ou d'un magazine.
Sous-type
Synthèse (review): revue aussi complète que possible des connaissances sur un sujet, rédigée à partir de l'analyse exhaustive des travaux publiés.
Collection
Publications
Titre
Regulation of the epithelial Na+ channel by Nedd4 and ubiquitination.
Périodique
Kidney International
Auteur(s)
Staub O., Abriel H., Plant P., Ishikawa T., Kanelis V., Saleki R., Horisberger J.D., Schild L., Rotin D.
ISSN
0085-2538
Statut éditorial
Publié
Date de publication
2000
Peer-reviewed
Oui
Volume
57
Numéro
3
Pages
809-815
Langue
anglais
Notes
Journal Article Research Support, Non-U.S. Gov't Review --- Old month value: Mar
Résumé
The epithelial Na+ channel (ENaC) is comprised of three subunits, alpha, beta and gamma, and plays an essential role in Na+ and fluid absorption in the kidney, colon and lung. We had identified proline-rich sequences at the C termini of alpha beta gamma ENaC, which include the sequence PPxY, the PY motif. This sequence in beta or gamma ENaC is deleted or mutated in Liddle's syndrome, a hereditary form of arterial hypertension. Our previous work demonstrated that these PY motifs bind to the WW domains of Nedd4, a ubiquitin protein ligase containing a C2 domain, three or four WW domains and a ubiquitin protein ligase Hect domain. Accordingly, we have recently demonstrated that Nedd4 regulates ENaC function by controlling the number of channels at the cell surface, that this regulation is impaired in ENaC bearing Liddle's syndrome mutations, and that ENaC stability and function are regulated by ubiquitination. The C2 domain is responsible for localizing Nedd4 to the plasma membrane in a Ca(2+)-dependent manner, and in polarized epithelial MDCK cells this localization is primarily apical. In accordance, electrophysiological characterization of ENaC expressed in MDCK cells revealed inhibition of channel activity by elevated intracellular Ca2+ levels. Thus, in response to Ca2+, Nedd4 may be mobilized to the apical membrane via its C2 domain, where it binds ENaC via Nedd4-WW:ENaC-PY motifs' interactions, leading to ubiquitination of the channel by the Nedd4-Hect domain and subsequent channel endocytosis and lysosomal degradation. This process may be at least partially impaired in Liddle's syndrome due to reduced Nedd4 binding, leading to increased retention of ENaC at the cell surface.
Mots-clé
Animals, Calcium, Calcium-Binding Proteins, Epithelial Sodium Channel, Epithelium, Humans, Hypertension, Ligases, Sodium Channels, Ubiquitin-Protein Ligases, Ubiquitins
Pubmed
Web of science
Création de la notice
24/01/2008 11:56
Dernière modification de la notice
03/03/2018 13:38
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