scholarly journals Liddle’s syndrome mutations disrupt cAMP-mediated translocation of the epithelial Na+ channel to the cell surface

2000 ◽  
Vol 105 (1) ◽  
pp. 45-53 ◽  
Author(s):  
Peter M. Snyder
Keyword(s):  
Cell Surface ◽  
Na Channel ◽  
Liddle’S Syndrome ◽  
Liddle's Syndrome ◽  
Epithelial Na Channel

scholarly journals Epithelial Na+ channel mutants causing Liddle's syndrome retain ability to respond to aldosterone and vasopressin

2003 ◽  
Vol 285 (3) ◽  
pp. F459-F471 ◽  
Author(s):  
Muriel Auberson ◽  
Nicole Hoffmann-Pochon ◽  
A. Vandewalle ◽  
Stephan Kellenberger ◽  
Laurent Schild
Keyword(s):  
Cell Surface ◽  
Collecting Duct ◽  
Short Circuit ◽  
Critical Role ◽  
Na Channel ◽  
Cortical Collecting Duct ◽  
Liddle’S Syndrome ◽  
Liddle's Syndrome ◽  
Py Motif ◽  
In Cells

Liddle's syndrome is a monogenic form of hypertension caused by mutations in the PY motif of the COOH terminus of β- and γ-epithelial Na+ channel (ENaC) subunits. These mutations lead to retention of active channels at the cell surface. Because of the critical role of this PY motif in the stability of ENaCs at the cell surface, we have investigated its contribution to the ENaC response to aldosterone and vasopressin. Mutants of the PY motif in β- and γ-ENaC subunits (β-Y618A, β-P616L, β-R564stop, and γ-K570stop) were stably expressed by retroviral gene transfer in a renal cortical collecting duct cell line (mpkCCDcl4), and transepithelial Na+ transport was assessed by measurements of the benzamil-sensitive short-circuit current ( Isc). Cells that express ENaC mutants of the PY motif showed a five- to sixfold higher basal Isc compared with control cells and responded to stimulation by aldosterone (10-6 M) or vasopressin (10-9 M) with a further increase in Isc. The rates of the initial increases in Isc after aldosterone or vasopressin stimulation were comparable in cells transduced with wild-type and mutant ENaCs, but reversal of the effects of aldosterone and vasopressin was slower in cells that expressed the ENaC mutants. The conserved sensitivity of ENaC mutants to stimulation by aldosterone and vasopressin together with the prolonged activity at the cell surface likely contribute to the increased Na+ absorption in the distal nephron of patients with Liddle's syndrome.

scholarly journals WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome.

1996 ◽  
Vol 15 (10) ◽  
pp. 2371-2380 ◽  
Author(s):  
O. Staub ◽  
S. Dho ◽  
P. Henry ◽  
J. Correa ◽  
T. Ishikawa ◽  
...  
Keyword(s):  
Na Channel ◽  
Ww Domains ◽  
Liddle’S Syndrome ◽  
Liddle's Syndrome ◽  
Epithelial Na Channel

scholarly journals Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel

Cell ◽  
1995 ◽  
Vol 83 (6) ◽  
pp. 969-978 ◽  
Author(s):  
Peter M. Snyder ◽  
Margaret P. Price ◽  
Fiona J. McDonald ◽  
Christopher M. Adams ◽  
Kenneth A. Volk ◽  
...  
Keyword(s):  
Na Channel ◽  
Liddle’S Syndrome ◽  
Liddle's Syndrome ◽  
Epithelial Na Channel

scholarly journals Liddle's syndrome: A novel mouse Nedd4 isoform regulates the activity of the epithelial Na+ channel

2001 ◽  
Vol 60 (2) ◽  
pp. 466-471 ◽  
Author(s):  
Elena Kamynina ◽  
Christophe Debonneville ◽  
Robert P. Hirt ◽  
Olivier Staub
Keyword(s):  
Na Channel ◽  
Liddle’S Syndrome ◽  
Liddle's Syndrome ◽  
Epithelial Na Channel

scholarly journals Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle's syndrome

1999 ◽  
Vol 103 (5) ◽  
pp. 667-673 ◽  
Author(s):  
Hugues Abriel ◽  
Johannes Loffing ◽  
John F. Rebhun ◽  
J. Howard Pratt ◽  
Laurent Schild ◽  
...  
Keyword(s):  
Na Channel ◽  
Liddle’S Syndrome ◽  
Liddle's Syndrome ◽  
Epithelial Na Channel

scholarly journals Inhibition of the Epithelial Na+Channel by Interaction of Nedd4 with a PY Motif Deleted in Liddle’s Syndrome

1998 ◽  
Vol 273 (45) ◽  
pp. 30012-30017 ◽  
Author(s):  
Christopher C. Goulet ◽  
Kenneth A. Volk ◽  
Christopher M. Adams ◽  
Lawrence S. Prince ◽  
John B. Stokes ◽  
...  
Keyword(s):  
Na Channel ◽  
Liddle’S Syndrome ◽  
Liddle's Syndrome ◽  
Py Motif ◽  
Epithelial Na Channel

scholarly journals Minireview: Regulation of Epithelial Na+ Channel Trafficking

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5079-5085 ◽  
Author(s):  
Peter M. Snyder
Keyword(s):  
Cell Surface ◽  
Collecting Duct ◽  
Distal Colon ◽  
Pressure Control ◽  
Na Channel ◽  
Na Transport ◽  
Channel Trafficking ◽  
C Terminus ◽  
Convergence Point ◽  
Epithelial Na Channel

The epithelial Na+ channel (ENaC) is a pathway for Na+ transport across epithelia, including the kidney collecting duct, lung, and distal colon. ENaC is critical for Na+ homeostasis and blood pressure control; defects in ENaC function and regulation are responsible for inherited forms of hypertension and hypotension and may contribute to the pathogenesis of cystic fibrosis and other lung diseases. An emerging theme is that epithelial Na+ transport is regulated in large part through trafficking mechanisms that control ENaC expression at the cell surface. ENaC trafficking is regulated at multiple steps. Delivery of channels to the cell surface is regulated by aldosterone (and corticosteroids) and vasopressin, which increase ENaC synthesis and exocytosis, respectively. Conversely, endocytosis and degradation is controlled by a sequence located in the C terminus of α, β, and γENaC (PPPXYXXL). This sequence functions as an endocytosis motif and as a binding site for Nedd4-2, an E3 ubiquitin protein ligase that targets ENaC for degradation. Mutations that delete or disrupt this motif cause accumulation of channels at the cell surface, resulting in Liddle’s syndrome, an inherited form of hypertension. Nedd4-2 is a central convergence point for ENaC regulation by aldosterone and vasopressin; both induce phosphorylation of a common set of three Nedd4-2 residues, which blocks Nedd4-2 binding to ENaC. Thus, aldosterone and vasopressin regulate epithelial Na+ transport in part by altering ENaC trafficking to and from the cell surface.

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