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|Title:||Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosic Na+|
|Citation:||Proceedings of the National Academy of Sciences of USA, 1998; 95(12):7169-7173|
|Publisher:||NATL ACAD SCIENCES|
|A. Dinudom, K. F. Harvey, P. Komwatana, J. A. Young, S. Kumar, and D. I. Cook|
|Abstract:||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.|
Endosomal Sorting Complexes Required for Transport
Nedd4 Ubiquitin Protein Ligases
|Appears in Collections:||Aurora harvest|
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