Acute Regulation of Epithelial Sodium Channel by Anionic Phospholipids

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Abstract
Anionic phospholipids such as phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) are normally located in the inner leaflet of the plasma membrane, where these anionic phospholipids can regulate transmembrane proteins, including ion channels and transporters. Recent work has demonstrated that (1) ATP inhibits the renal epithelial sodium channel (ENaC) via a phospholipase C–dependent pathway that reduces PIP2, (2) aldosterone stimulates ENaC via phosphoinositide 3-kinase, and (3) PIP2 and PIP3 regulate ENaC. Several lines of evidence show that ATP stimulation of purinergic P2Y receptors hydrolyzes PIP2 and that aldosterone stimulation of steroid receptors induces PIP3 formation. These studies together suggest that one primary mechanism for regulating ENaC is by alteration of anionic phospholipids and that the receptor-mediated and hormonal regulation of ENaC works through a variety of signaling pathways, but many of these pathways finally alter ENaC activity by regulating the formation or degradation of anionic phospholipids. Therefore, changes in the concentration of PIP2 and PIP3 are hypothesized to participate in the regulation of ENaC by purinergic and corticoid receptors. The underlying mechanism may be associated with a physical interaction of the positively charged cytoplasmic domains of the β- and γ-ENaC with the negatively charged membrane phospholipids. The exact nature of this interaction will require further investigation.

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