ENaC regulation by phospholipids and DGK explained through mathematical modeling

• Published in: Scientific reports Vol. 10; no. 1; p. 13952
• Main Authors: Olivença, Daniel V., Voit, Eberhard O., Pinto, Francisco R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.08.2020; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol-4-phosphate 5-kinase; 631/114/2397; 631/443/1784; 631/553/2695; 692/699/1785/4039; Computational Biology - methods; Computer applications; Cystic fibrosis; Cystic Fibrosis - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Diacylglycerol kinase; Diacylglycerol Kinase - antagonists & inhibitors; Diacylglycerol Kinase - metabolism; Epithelial Sodium Channels - metabolism; Humanities and Social Sciences; Humans; Inositol Phosphates - metabolism; Ion channels; Ion Transport; Lipids; Mathematical models; Membrane proteins; Models, Biological; multidisciplinary; Phosphatidic acid; Phosphatidylinositol 4,5-diphosphate; Phosphoinositides; Phospholipids; Phospholipids - metabolism; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Science; Science (multidisciplinary); Signal Transduction; Sodium; Sodium channels
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-70630-w

Cystic fibrosis is a condition caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). It is also thought to increase the activity of epithelial sodium channels (ENaC). The altered function of these ion channels is one of the causes of the thick dehydrated mucus that characterizes the disease and is partially responsible for recurrent pulmonary infections and inflammation events that ultimately destroy the lungs of affected subjects. Phosphoinositides are signaling lipids that regulate numerous cellular processes and membrane proteins, including ENaC. Inhibition of diacylglycerol kinase (DGK), an enzyme of the phosphoinositide pathway, reduces ENaC function. We propose a computational analysis that is based on the combination of two existing mathematical models: one representing the dynamics of phosphoinositides and the other explaining how phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) influences ENaC activity and, consequently, airway surface liquid. This integrated model permits, for the first time, a detailed assessment of the intricate interactions between DGK and ENaC and is consistent with available literature data. In particular, the computational approach allows comparisons of two competing hypotheses regarding the regulation of ENaC. The results strongly suggest that the regulation of ENaC is primarily exerted through the control of PI(4,5)P 2 production by type-I phosphatidylinositol-4-phosphate 5-kinase (PIP5KI), which in turn is controlled by phosphatidic acid (PA), the product of the DGK reaction.