Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+.
Epithelial Na+ channels are expressed widely in absorptive epithelia such as the renal collecting duct and the colon and play a critical role in fluid and electrolyte homeostasis. Recent studies have shown that these channels interact via PY motifs in the C terminals of their alpha, beta, and gamma subunits with the WW domains of the ubiquitin-protein ligase Nedd4. Mutation or deletion of these PY motifs (as occurs, for example, in the heritable form of hypertension known as Liddle's syndrome) leads to increased Na+ channel activity. Thus, binding of Nedd4 by the PY motifs would appear to be part of a physiological control system for down-regulation of Na+ channel activity. The nature of this control system is, however, unknown. In the present paper, we show that Nedd4 mediates the ubiquitin-dependent down-regulation of Na+ channel activity in response to increased intracellular Na+. We further show that Nedd4 operates downstream of Go in this feedback pathway. We find, however, that Nedd4 is not involved in the feedback control of Na+ channels by intracellular anions. Finally, we show that Nedd4 has no influence on Na+ channel activity when the Na+ and anion feedback systems are inactive. We conclude that Nedd4 normally mediates feedback control of epithelial Na+ channels by intracellular Na+, and we suggest that the increased Na+ channel activity observed in Liddle's syndrome is attributable to the loss of this regulatory feedback system.
Dinudom
A
A
Department of Physiology, University of Sydney, Sydney, New South Wales 2006, Australia.
Harvey
K F
KF
Komwatana
P
P
Young
J A
JA
Kumar
S
S
Cook
D I
DI
D000818:Animals; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport; D004847:Epithelial Cells / Q000502:physiology*; D008025:Ligases; D008297:Male; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D018987:Salivary Ducts / Q000502:physiology*; D012964:Sodium / Q000502:physiology*; D015222:Sodium Channels / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
D002135:Calcium-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D015222:Sodium Channels; D012964:Sodium; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D008025:Ligases