Acute regulation of epithelial sodium channel by anionic phospholipids.
Anionic phospholipids such as phosphatidylinositol 4,5-bisphosphate (PIP(2)) and phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) 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 PIP(2), (2) aldosterone stimulates ENaC via phosphoinositide 3-kinase, and (3) PIP(2) and PIP(3) regulate ENaC. Several lines of evidence show that ATP stimulation of purinergic P2Y receptors hydrolyzes PIP(2) and that aldosterone stimulation of steroid receptors induces PIP(3) 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 PIP(2) and PIP(3) 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 beta- and gamma-ENaC with the negatively charged membrane phospholipids. The exact nature of this interaction will require further investigation.
Ma
He-Ping
HP
Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, 1530 Third Avenue South, Sparks Center 865, Birmingham, AL 35294, USA. hepingma@uab.edu
Eaton
Douglas C
DC
D000595:Amino Acid Sequence; D000818:Animals; D000838:Anions; D001665:Binding Sites; D053503:Epithelial Sodium Channels; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry; D011983:Receptors, Purinergic / Q000502:physiology; D011987:Receptors, Steroid / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D019459:Urothelium / Q000502:physiology
D000838:Anions; D053503:Epithelial Sodium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D010743:Phospholipids; D020033:Protein Isoforms; D011983:Receptors, Purinergic; D011987:Receptors, Steroid; D015222:Sodium Channels