Pharmacology of Phosphoinositides, Regulators of Multiple Cellular Functions

Inositol phospholipids represent a small fraction of the phospholipids present in all cellular membranes with remarkable importance in regulating various cell functions. They are synthesized from phosphatidylinositol by sequential phosphorylations on the several hydroxyls of the inositol ring to create polyphos-phoinositides that function either as docking sites to promote formation of molecular signaling complexes, or serve as precursors for soluble inositol polyphosphates that act as diffusible intracellular messengers. Phosphoinositides are involved in the control of many processes, including membrane traffic, endo- and exocytosis, mitogenesis and apoptosis. Pharmacological tools have helped to clarify many details of phosphoinositide metabolism and have unveiled the roles of these lipids in the control of specific signaling pathways. However, because of their pleiotropic functions it has been questionable whether pharmacological manipulation of inositide formation and metabolism can be of therapeutic value. This review briefly summarizes the means by which inositide functions have been pharmacologically manipulated, and discusses possibilities for specifically targeting certain aspects of their regulatory functions.