Abstract
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)P2) 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)P2 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.
Highlights
The reasons for ENaC’s upregulation in cystic fibrosis (CF) are not clear, but there is no shortage of hypotheses[3,4,5,6,7,8,9]
The phosphoinositide pathway module was adapted from our recent work[24] and expanded with processes that are fundamental to the regulation of the pathway
Several results in the literature support our hypothesis that phosphatidylinositol-4-phosphate 5-kinase (PIP5KI) regulation by phosphatidic acid (PA) explains the moderation of ENaC activity induced by Diacylglycerol kinase (DGK) knockdown, as Almaça et al.[21] had observed
Summary
The reasons for ENaC’s upregulation in CF are not clear, but there is no shortage of hypotheses[3,4,5,6,7,8,9]. ENaC channels have a lower probability of being removed from the plasma membrane and, ENaC function is up-regulated. We adopted this view because it was at least partially validated by results obtained under physiologically and clinically relevant c onditions[14]. Several studies have shown that two of these lipids, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3), have an effect on E NaC17–19 Their key precursor, phosphatidylinositol (PI), is created in the ER from phosphatidic acid (PA) and transported to the plasma membrane, where it is phosphorylated into other phosphoinositide species (Fig. 1, upper box). By phospholipase C (PLC) into inositol triphosphate (IP3) and diacylglycerol (DAG) and transformed into PA, which is transported back to the ER, closing a functional cycle
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