Regulation of the epithelial Na+ channel (ENaC) by phosphatidylinositides

Oleh Pochynyuk, Qiusheng Tong, Alexander Staruschenko, He Ping Ma, James D. Stockand

Research output: Contribution to journalReview articlepeer-review

67 Scopus citations


The epithelial Na+ channel (ENaC) is an end-effector of diverse cellular signaling cascades, including those with phosphatidylinositide second messengers. Recent evidence also suggests that in some instances, phospatidylinositides can directly interact with ENaC to increase channel activity by increasing channel open probability and/or membrane localization. We review here findings relevant to regulation of ENaC by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-triphosphate (PIP3). Similar to its actions on other ion channels, PIP2 is permissive for ENaC openings having a direct effect on gating. The PIP 2 binding site in ENaC involved in this regulation is most likely localized to the NH2 terminus of β-ENaC. PIP3 also affects ENaC gating but, rather than being permissive, augments open probability. The PIP3 binding site in ENaC involved in this regulation is localized to the proximal region of the COOH terminus of γ-ENaC just following the second transmembrane domain. In complementary pathways, PIP3 also impacts ENaC membrane levels through both direct actions on the channel and via a signaling cascade involving phosphoinositide 3-OH kinase (PI3-K) and the aldosterone-induced gene product serum and glucocorticoid-inducible kinase. The putative PIP3 binding site in ENaC involved in direct regulation of channel membrane levels has not yet been identified.

Original languageEnglish (US)
Pages (from-to)F949-F957
JournalAmerican Journal of Physiology - Renal Physiology
Issue number5
StatePublished - May 2006


  • Insulin G protein-coupled receptor
  • Phosphatidylinositol 3,4,5-triphosphate
  • Phosphatidylinositol 4,5-bisphosphate
  • Receptor tyrosine kinase

ASJC Scopus subject areas

  • Urology
  • Physiology


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