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 beta- and gamma-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.