Inositol phosphate metabolism and signal transduction

Activation of a variety of cell surface receptors results in a biphasic increase in the cytoplasmic Ca2+ concentration, due to the release or mobilization of intracellular Ca2+ stores and to the entry of Ca2+ from the extracellular space. Stimulation of these same receptors also results in the hydrolysis of the minor plasma membrane phospholipid, phosphatidylinositol 4,5-bisphosphate, with the concomitant formation of (1,4,5)inositol trisphosphate [(1,4,5)IP3] and diacylglycerol. It is well established that phosphatidylinositol 4,5-bisphosphate hydrolysis is responsible for the changes in Ca2+ homeostasis. There is strong evidence that (1,4,5)IP3 stimulates Ca2+ release from intracellular stores. The Ca2(+)-releasing actions of (1,4,5)IP3 are terminated by its metabolism through two distinct pathways: (1,4,5)IP3 is dephosphorylated by a 5-phosphatase to (1,4)IP2; alternatively, (1,4,5)IP3 is phosphorylated to (1,3,4,5)IP4 by a 3-kinase. Whereas the mechanism of Ca2+ mobilization is understood, the precise mechanisms involved in Ca2+ entry are not known. A recent proposal that (1,4,5)IP3, by emptying an intracellular Ca2+ pool, secondarily elicits Ca2+ entry will be considered. This review summarizes recent studies of the mechanisms by which inositol phosphates regulate cytoplasmic Ca2+ concentrations.