Regulation of the epithelial sodium channel by accessory proteins

Biochem J. 2003 Apr 1;371(Pt 1):1-14. doi: 10.1042/BJ20021375.


The epithelial sodium channel (ENaC) is of fundamental importance in the control of sodium fluxes in epithelial cells. Modulation of sodium reabsorption through the distal nephron ENaC is an important component in the overall control of sodium balance, blood volume and thereby of blood pressure. This is clearly demonstrated by rare genetic disorders of sodium-channel activity (Liddle's syndrome and pseudohypoaldosteronism type 1), associated with contrasting effects on blood pressure. The mineralocorticoid aldosterone is a well-established modulator of sodium-channel activity. Considerable insight has now been gained into the intracellular signalling pathways linking aldosterone-mediated changes in gene transcription with changes in ion transport. Activating pathways include aldosterone-induced proteins and especially the serum- and glucocorticoid-inducible kinase (SGK) and the small G-protein, K-Ras 2A. Targeting of the ENaC for endocytosis and degradation is now emerging as a major mechanism for the down-regulation of channel activity. Several proteins acting in concert are an intrinsic part of this process but Nedd4 (neural precursor cell expressed developmentally down-regulated 4) is of central importance. Other mechanisms known to interact with ENaC and affect sodium transport include channel-activating protease 1 (CAP-1), a membrane-anchored protein, and the cystic fibrosis transmembrane regulator. The implications of research on accessory factors controlling ENaC activity are wide-ranging. Understanding cellular mechanisms controlling ENaC activity may provide a more detailed insight not only of ion-channel abnormalities in cystic fibrosis but also of the link between abnormal renal sodium transport and essential hypertension.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Clathrin / metabolism
  • Endocytosis / physiology
  • Endosomal Sorting Complexes Required for Transport
  • Epithelial Sodium Channels
  • Humans
  • Hypertension / genetics
  • Immediate-Early Proteins
  • Kidney Diseases / genetics
  • Kidney Diseases / physiopathology
  • Ligases / genetics
  • Ligases / metabolism
  • Mineralocorticoids / metabolism
  • Molecular Sequence Data
  • Mutation
  • Nedd4 Ubiquitin Protein Ligases
  • Nuclear Proteins*
  • Protein Structure, Tertiary / physiology
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Sodium Channels / chemistry
  • Sodium Channels / genetics*
  • Sodium Channels / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases*


  • Calcium-Binding Proteins
  • Clathrin
  • Endosomal Sorting Complexes Required for Transport
  • Epithelial Sodium Channels
  • Immediate-Early Proteins
  • Mineralocorticoids
  • Nuclear Proteins
  • Proteins
  • Sodium Channels
  • Ubiquitin
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, human
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • Ligases