Binding and direct activation of the epithelial Na + channel (ENaC) by phosphatidylinositides

Several distinct types of ion channels bind and directly respond to phosphatidylinositides, including phosphatidylinositol (3,4,5)‐trisphosphate (PI(3,4,5)P 3 ) and phosphatidylinositol (4,5)‐bisphosphate (PI(4,5)P 2 ). This regulation is physiologically relevant for its dysfunction, in some instances, causes disease. Recent studies identify the epithelial Na + channel (ENaC) as a channel sensitive to phosphatidylinositides. ENaC appears capable of binding both PI(4,5)P 2 and PI(3,4,5)P 3 with binding stabilizing channel gating. The binding sites for these molecules within ENaC are likely to be distinct with the former phosphoinositide interacting with elements in the cytosolic NH 2 ‐terminus of the β‐ and γ‐ENaC subunits and the latter with cytosolic regions immediately following the second transmembrane domains in these two subunits. PI(4,5)P 2 binding to ENaC appears saturated at rest and necessary for channel gating. Thus, decreases in cellular PI(4,5)P 2 levels may serve as a convergence point for inhibitory regulation of ENaC by G‐protein coupled receptors and receptor tyrosine kinases. In contrast, apparent PI(3,4,5)P 3 binding to ENaC is not saturated. This enables the channel to respond with gating changes in a rapid and dynamic manner to signalling input that influences cellular PI(3,4,5)P 3 levels.