Titre
ENaC and its regulatory proteins as drug targets for blood pressure control.
Type
synthèse (review)
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Rotin, D.
Auteure/Auteur
Schild, L.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1873-5592[electronic]
Statut éditorial
Publié
Date de publication
2008
Volume
9
Numéro
8
Première page
709
Dernière page/numéro d’article
716
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Review
Résumé
Hypertension is a serious medical problem affecting millions of people worldwide. A key protein regulating blood pressure is the Epithelial Na(+) Channel (ENaC). In accord, loss of function mutations in ENaC (PHA1) cause hypotension, whereas gain of function mutations (Liddle syndrome) result in hypertension. The region mutated in Liddle syndrome, called the PY motif (L/PPxY), serves as a binding site for the ubiquitin ligase Nedd4-2, a C2-WW-Hect E3 ubiquitin ligase. Nedd4-2 binds the ENaC-PY motif via it WW domains, ubiquitylates the channel and targets it for endocytosis, a process impaired in Liddle syndrome due to poor binding of the channel to Nedd4-2. This leads to accumulation of active channels at the cell surface and increased Na(+) (and fluid) absorption in the distal nephron, resulting in elevated blood volume and blood pressure. Compounds that destabilize cell surface ENaC, or enhance Nedd4-2 activity in the kidney, could potentially serve as drug targets for hypertension. In addition, recent discoveries of regulation of activation of ENaC by proteases such as furin, prostasin and elastase, which cleave the extracellular domain of this channel leading to it activation, as well as the identification of inhibitors that block the activity of these proteases, provide further avenues for drug targeting of ENaC and the control of blood pressure.
PID Serval
serval:BIB_1D8095F56770
PMID
Date de création
2009-10-30T11:33:52.791Z
Date de création dans IRIS
2025-05-20T14:53:46Z