Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+.

  • Dinudom A
  • Harvey K
  • Komwatana P
 et al. 
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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.

Author-supplied keywords

  • Animals
  • Calcium-Binding Proteins
  • Calcium-Binding Proteins: physiology
  • Cells, Cultured
  • Endosomal Sorting Complexes Required for Transport
  • Epithelial Cells
  • Epithelial Cells: physiology
  • Ligases
  • Male
  • Mice
  • Salivary Ducts
  • Salivary Ducts: physiology
  • Sodium
  • Sodium Channels
  • Sodium Channels: physiology
  • Sodium: physiology
  • Ubiquitin-Protein Ligases

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  • A Dinudom

  • K F Harvey

  • P Komwatana

  • J A Young

  • S Kumar

  • D I Cook

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