Titre
Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Schild, L.
Auteure/Auteur
Lu, Y.
Auteure/Auteur
Gautschi, I.
Auteure/Auteur
Schneeberger, E.
Auteure/Auteur
Lifton, R. P.
Auteure/Auteur
Rossier, B. C.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
0261-4189
Statut éditorial
Publié
Date de publication
1996-05
Volume
15
Numéro
10
Première page
2381
Dernière page/numéro d’article
7
Peer-reviewed
Oui
Notes
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: May 15
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: May 15
Résumé
Liddle syndrome is an autosomal dominant form of hypertension, resulting from mutations in the cytoplasmic C-terminus of either the beta or gamma subunits of the amiloride-sensitive epithelial Na channel (ENaC) which lead to constitutively increased channel activity. Most mutations reported to date result in the elimination of 45-75 normal amino acids from these segments, leaving open the question of the identity of the precise amino acids in which mutation can lead to an enhanced channel activity. To address this question, we have performed a systematic mutagenesis study of the C-termini of the alpha, beta and gamma ENaC subunits of the rat channel and have analyzed their function by expression in Xenopus oocytes. The results demonstrate that a short proline-rich segment present in the cytoplasmic C-terminus of each subunit is required for the normal regulation of channel activity. Missense mutations altering a consensus PPPXY sequence of the alpha, beta or gamma subunits reproduced the increase in channel activity found in mutants in which the entire cytoplasmic C-termini are deleted. This proline-rich sequence, referred to as the PY motif, is known to be a site of binding by proteins bearing a WW domain. These findings show that the three PY motifs in the C-termini of ENaC are involved in the regulation of channel activity, probably via protein-protein interactions. This new regulatory mechanism of channel function is critical for the maintenance of normal Na reabsorption in the kidney and of Na+ balance and blood pressure.
Sujets
PID Serval
serval:BIB_F99224DF3C2A
PMID
Date de création
2008-01-24T12:01:19.873Z
Date de création dans IRIS
2025-05-21T05:16:02Z