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)P₃) and phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P₂). 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)P₂ and PI(3,4,5)P₃ 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 NH₂-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)P₂ binding to ENaC appears saturated at rest and necessary for channel gating. Thus, decreases in cellular PI(4,5)P₂ 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)P₃ 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)P₂ levels.