Organization of the ENaC-regulatory machinery

Crit Rev Biochem Mol Biol. Jul-Aug 2012;47(4):349-59. doi: 10.3109/10409238.2012.678285. Epub 2012 Apr 16.


The control of fluid and electrolyte homeostasis in vertebrates requires the integration of a diverse set of signaling inputs, which control epithelial Na(+) transport, the principal ionic component of extracellular fluid. The key site of regulation is a segment of the kidney tubules, frequently termed the aldosterone-sensitive distal nephron, wherein the epithelial Na(+) channel (or ENaC) mediates apical ion entry. Na(+) transport in this segment is strongly regulated by the salt-retaining hormone, aldosterone, which acts through the mineralocorticoid receptor (MR) to influence the expression of a selected set of target genes, most notably the serine-threonine kinase SGK1, which phosphorylates and inhibits the E3 ubiquitin ligase Nedd4-2. It has long been known that ENaC activity is tightly regulated in vertebrate epithelia. Recent evidence suggests that SGK1 and Nedd4-2, along with other ENaC-regulatory proteins, physically associate with each other and with ENaC in a multi-protein complex. The various components of the complex are regulated by diverse signaling networks, including steroid receptor-, PI3-kinase-, mTOR-, and Raf-MEK-ERK-dependent pathways. In this review, we focus on the organization of the targets of these pathways by multi-domain scaffold proteins and lipid platforms into a unified complex, thereby providing a molecular basis for signal integration in the control of ENaC.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Aldosterone / metabolism
  • Animals
  • Epithelial Sodium Channels / genetics
  • Epithelial Sodium Channels / metabolism*
  • Humans
  • Membrane Microdomains / metabolism
  • Nuclear Matrix-Associated Proteins / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology*


  • Epithelial Sodium Channels
  • Nuclear Matrix-Associated Proteins
  • Aldosterone