Liddle's syndrome: a novel mouse Nedd4 isoform regulates the activity of the epithelial Na(+) channel.
The epithelial Na(+) channel (ENaC), which plays an essential role in renal Na(+) handling, is composed of three subunits (alpha beta gamma), each containing a conserved PY motif at the C terminus. In Liddle's syndrome, an inherited form of salt-sensitive hypertension, the PY motifs of either beta or gamma ENaC are deleted or modified. We have recently shown that a ubiquitin-protein ligase Nedd4 binds via its WW domains to these PY motifs on ENaC, that ENaC is regulated by ubiquitination, and that Xenopus laevis Nedd4 (xNedd4) controls the cell surface pool of ENaC when coexpressed in Xenopus oocytes. Interestingly, Na(+) transporting cells, derived from mouse cortical collecting duct, express two different Nedd4 isoforms, which we have termed mNedd4-1 and mNedd4-2. Only mNedd4-2, which is orthologous to xNedd4, but not mNedd4-1, is able to regulate ENaC activity, and this property correlates with the capability to bind to the ENaC complex. Hence, Nedd4-2 may be encoded by a novel susceptibility gene for arterial hypertension.
Kamynina
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E
Institute of Pharmacology and Toxicology, University of Lausanne, Switzerland.
Debonneville
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C
Hirt
R P
RP
Staub
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O
D000818:Animals; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D007536:Isomerism; D007668:Kidney / Q000378:metabolism*; D008025:Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D015222:Sodium Channels / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D029867:Xenopus Proteins
D002135:Calcium-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D015222:Sodium Channels; D029867:Xenopus Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618482:Nedd4 protein, Xenopus; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; C000618461:Nedd4l protein, mouse; C000618460:nedd4l protein, Xenopus; D044767:Ubiquitin-Protein Ligases; D008025:Ligases