title: Mutations causing Liddle syndrome reduce sodium-dependent downregulation of the epithelial sodium channel in the Xenopus oocyte expression system.
abstract: Liddle syndrome is an autosomal dominant form of hypertension resulting from deletion or missense mutations of a PPPxY motif in the cytoplasmic COOH terminus of either the beta or gamma subunit of the epithelial Na channel (ENaC). These mutations lead to increased channel activity. In this study we show that wild-type ENaC is downregulated by intracellular Na+, and that Liddle mutants decrease the channel sensitivity to inhibition by intracellular Na+. This event results at high intracellular Na+ activity in 1.2-2.4-fold higher cell surface expression, and 2.8-3.5-fold higher average current per channel in Liddle mutants compared with the wild type. In addition, we show that a rapid increase in the intracellular Na+ activity induced downregulation of the activity of wild-type ENaC, but not Liddle mutants, on a time scale of minutes, which was directly correlated to the magnitude of the Na+ influx into the oocytes. Feedback inhibition of ENaC by intracellular Na+ likely represents an important cellular mechanism for controlling Na+ reabsorption in the distal nephron that has important implications for the pathogenesis of hypertension.
authors.affiliation: Institut de Pharmacologie et de Toxicologie, Université de Lausanne, 1005 Lausanne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Kellenberger
authors.forename: I
authors.initials: I
authors.lastname: Gautschi
authors.forename: B C
authors.initials: BC
authors.lastname: Rossier
authors.forename: L
authors.initials: L
authors.lastname: Schild
mesh_terms: D000818:Animals; D015536:Down-Regulation; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D009154:Mutation; D051381:Rats; D012964:Sodium / Q000502:physiology*; D015222:Sodium Channels / Q000235:genetics*; D014162:Transfection; D014981:Xenopus
chemical_list: D015222:Sodium Channels; D012964:Sodium