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Acute Regulation of Epithelial Sodium Channel by Anionic Phospholipids

He-Ping Ma^* and Douglas C. Eaton

^* Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Alabama; Department of Physiology, Emory University of School of Medicine, Atlanta, Georgia

Address correspondence to: Dr. He-Ping Ma, Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, 1530 Third Avenue South, Sparks Center 865, Birmingham, AL 35294. Phone: 205-934-3806; Fax: 205-934-1147; E-mail: hepingma{at}uab.edu

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 - and -ENaC with the negatively charged membrane phospholipids. The exact nature of this interaction will require further investigation.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673