Phosphorylation of Nedd4‐2 by Sgk1 regulates epithelial Na+ channel cell surface expression
Christophe Debonneville,Christophe Debonneville,Sandra Y. Flores,Sandra Y. Flores,Elena Kamynina,Pamela J. Plant,Caroline Tauxe,Marc A. Thomas,Carole Münster,Ahmed Chraibi,J. Howard Pratt,Jean-Daniel Horisberger,David A. Pearce,Johannes Loffing,Olivier Staub +14 more
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TLDR
It is shown that phosphorylation of an enzyme involved in the ubiquitylation cascade (Nedd4‐2) controls cell surface density of ENaC and a paradigm for the control of ion channels is proposed.Abstract:
The epithelial Na+ channel (ENaC) plays an essential role in the regulation of whole body Na+ balance and blood pressure. The cell surface expression of this channel, a complex of three subunits (α, β and γENaC), has been shown to be regulated by hormones such as aldosterone and vasopressin and by intracellular signaling, including ubiquitylation and/or phosphorylation. However, the molecular mechanisms involving phosphorylation in the regulation of ENaC are unclear. Here we show by expression studies in Xenopus laevis oocytes that the aldosterone-induced Sgk1 kinase interacts with the ubiquitin protein ligase Nedd4-2 in a PY motif-dependent manner and phosphorylates Nedd4-2 on Ser444 and, to a lesser extent, Ser338. Such phosphorylation reduces the interaction between Nedd4-2 and ENaC, leading to elevated ENaC cell surface expression. These data show that phosphorylation of an enzyme involved in the ubiquitylation cascade (Nedd4-2) controls cell surface density of ENaC and propose a paradigm for the control of ion channels. Moreover, they suggest a novel and complete signaling cascade for aldosterone-dependent regulation of ENaC.read more
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References
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Journal ArticleDOI
Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.
Cecilia M. Canessa,Laurent Schild,Gary Buell,Bernard Thorens,Ivan Gautschi,Jean-Daniel Horisberger,Bernard C. Rossier +6 more
TL;DR: The ion-selective permeability, the gating properties and the pharmacological profile of the channel formed by coexpressing the three subunits in oocytes are similar to that of the native channel.
Journal ArticleDOI
Liddle's syndrome: Heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel
Richard A. Shimkets,David G. Warnock,Christopher M. Bositis,Carol Nelson-Williams,Joni H. Hansson,Morris Schambelan,John R. Gill,Stanley Ulick,Robert V. Milora,James W. Findling,Cecilia M. Canessa,Bernard C. Rossier,Richard P. Lifton +12 more
TL;DR: It is demonstrated that Liddle's syndrome is caused by mutations in the beta subunit of the epithelial sodium channel and have implications for the regulation of this epithelial ion channel as well as blood pressure homeostasis.
Journal ArticleDOI
Epithelial sodium channels: function, structure, and regulation
H. Garty,Lawrence G. Palmer +1 more
TL;DR: The apical (outward-facing) membranes of high-resistance epithelia contain Na+ channels, traditionally identified by their sensitivity to block by the K(+)-sparing diuretic amiloride, which mediate the first step of active Na+ reabsorption and play a major role in the maintenance of electrolyte and water homeostasis in all vertebrates.
Journal ArticleDOI
Epithelial sodium channel related to proteins involved in neurodegeneration
TL;DR: The gene encoding this rat sodium channel subunit shares significant sequence similarity with mec-4 and deg-1, members of a family of Caenorhabditis elegans genes involved in sensory touch transduction and, when mutated, neuronal degeneration, and it is proposed that the gene products of these three genes are member of a gene family coding for cation channels.
Journal ArticleDOI
WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome.
TL;DR: The results demonstrate that the WW domains of rNedd4 bind to the PY motifs deleted from beta or gammaENaC in Liddle's syndrome patients, and suggest that Nedd4 may be a regulator (suppressor) of the epithelial Na+ channel.