Phosphoinositide lipid second messengers: new paradigms for transepithelial signal transduction

Multiple forms of phosphatidylinositol are generated by differential phosphorylation of the inositol headgroup. These phosphoinositides, specifically PI(4,5)P2, have been implicated as modulators in a variety of transport processes. The data indicate that phosphoinositides can modulate transporters directly or via the activation of down-stream signaling components. The phosphoinositide pathway has been linked to changes in transporter kinetics, intracellular signaling, membrane targeting and membrane stability. Recent results obtained for several of the well-characterized transport systems suggest the need to reassess the role of PI(4,5)P2 and question whether lower abundance forms of the phosphoinositides, notably PI(3,4,5)P3 (PIP3) and PI(3,4)P2, are the pertinent transport regulators. In contrast to PI(4,5)P2, these latter forms represent a dynamic, regulated pool, the characteristics of which are more compatible with the nature of signaling intermediates. A recently described, novel transepithelial signaling pathway has been demonstrated for PIP3 in which a signal initiated on the basolateral membrane is transduced to the apical membrane entirely within the planar face of the inner leaflet of the plasma membrane. The new paradigms emerging from recent studies may be widely applicable to transporter regulation in other cell types and are particularly relevant for signaling in polarized cells.