The Complex and Intriguing Lives of PIP₂ with Ion Channels and Transporters

Donald W. Hilgemann^*, Siyi Feng, and Cem Nasuhoglu

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9040 USA.

Gloss: Phosphatidylinositol-4,5-bisphosphate (PIP₂), a minor phospholipid in the surface membrane of eukaryotic cells, serves as the precursor of several signaling molecules. It is now also clear, however, that PIP₂ itself is used by cells to anchor numerous membrane-associated proteins and to regulate membrane-associated processes. The local concentration of PIP₂ in the plasma membrane may change during various cell-signaling events, and these changes may then alter the activity of PIP₂-binding proteins. Several cytoskeletal proteins are known to be modulated by PIP₂, and numerous ion channels, ion pumps, and ion exchangers have now also been found to be PIP₂ targets. Recently, changes in PIP₂ have been implicated in regulating sensory ion channels, such as those involved in pain perception and phototransduction. In the surface membrane, PIP₂ may be restricted to microdomains called "lipid rafts", and thus, PIP₂ may serve to localize its binding partners to subdomains of the membrane. Because the activity of proteins can be controlled by the level of PIP₂, differences in the concentration of this phospholipid between membranes of the secretory pathway and the plasma membrane may help control the activity of ion transporters during biosynthesis or during vesicle trafficking. Thus, PIP₂ may not only be used as a signal to regulate cellular membrane trafficking; it may also control protein activity during trafficking. Clearly, PIP₂, like other cell signaling molecules, can be used by cells in multiple ways. Modulation of ion channel and transporter activities in response to stimuli that alter membrane lipid composition appears to be an important role of PIP₂ in eukaryotic cell life.

*Corresponding author, Telephone: 214-648-6728, fax: 214-648-8879, e-mail: hilgeman{at}utsw.swmed.edu

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