Regulation of the epithelial sodium channel by phosphatidylinositides: experiments, implications, and speculations.
Recent studies suggest that the activity of epithelial sodium channels (ENaC) is increased by phosphatidylinositides, especially phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P(3)). Stimulation of phospholipase C by either adenosine triphosphate (ATP)-activation of purinergic P2Y receptors or epidermal growth factor (EGF)-activation of EGF receptors reduces membrane PI(4,5)P(2), and consequently decreases ENaC activity. Since ATP and EGF may be trapped in cysts formed by the distal tubule, it is possible that ENaC inhibition induced by ATP and EGF facilitates cyst formation in polycystic kidney diseases (PKD). However, some results suggest that ENaC activity is increased in PKD. In contrast to P2Y and EGF receptors, stimulation of insulin-like growth factor-1 (IGF-1) receptor by aldosterone or insulin produces PI(3,4,5)P(3), and consequently increases ENaC activity. The acute effect of aldosterone on ENaC activity through PI(3,4,5)P(3) possibly accounts for the initial feedback for blood volume recovery after hypovolemic hypotension. PI(4,5)P(2) and PI(3,4,5)P(3), respectively, interacts with the N terminus of beta-ENaC and the C terminus of gamma-ENaC. However, whether ENaC selectively binds to PI(4,5)P(2) and PI(3,4,5)P(3) over other anionic phospholipids remains unclear.
Ma
He-Ping
HP
Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, 1530 Third Avenue South, ZRB 510, Birmingham, AL, 35294, USA. hepingma@uab.edu
Chou
Chu-Fang
CF
Wei
Shi-Peng
SP
Eaton
Douglas C
DC
D000595:Amino Acid Sequence; D000818:Animals; D053503:Epithelial Sodium Channels / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D008969:Molecular Sequence Data; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000494:pharmacology*; D013268:Stimulation, Chemical; D010738:Type C Phospholipases / Q000378:metabolism
D053503:Epithelial Sodium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases