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Regulation of the epithelial sodium channel by phosphatidylinositides: experiments, implications, and speculations

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Abstract

Recent studies suggest that the activity of epithelial sodium channels (ENaC) is increased by phosphatidylinositides, especially phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3). 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)P2, 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)P3, and consequently increases ENaC activity. The acute effect of aldosterone on ENaC activity through PI(3,4,5)P3 possibly accounts for the initial feedback for blood volume recovery after hypovolemic hypotension. PI(4,5)P2 and PI(3,4,5)P3, respectively, interacts with the N terminus of β-ENaC and the C terminus of γ-ENaC. However, whether ENaC selectively binds to PI(4,5)P2 and PI(3,4,5)P3 over other anionic phospholipids remains unclear.

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Acknowledgement

H.-P.M. was supported by DHHS, National Institutes of Health (NIH) Grant R01-DK067110 and D.C.E by NIH Grant R37-DK37963, P30-DK064399, and P01-DK61521.

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  1. Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, 1530 Third Avenue South, ZRB 510, Birmingham, AL, 35294, USA

    He-Ping Ma, Chu-Fang Chou & Shi-Peng Wei

  2. Department of Physiology, Emory University of School of Medicine, Atlanta, GA, 30322, USA

    Douglas C. Eaton

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Ma, HP., Chou, CF., Wei, SP. et al. Regulation of the epithelial sodium channel by phosphatidylinositides: experiments, implications, and speculations. Pflugers Arch - Eur J Physiol 455, 169–180 (2007). https://doi.org/10.1007/s00424-007-0294-3

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