Inositol phospholipids and cell regulation.

The increased turnover of phosphatidylinositol (PtdIns) in response to activation of cell-surface receptors was discovered by Hokin & Hokin (1953). The structures of the so-called polyphosphoinositides, phosphatidylinositol 4-phosphate (Ptdlns4P) and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], were not elucidated until the next decade, but their metabolic importance was suggested by their rapid incorporation of 32P (Dawson, 1954). This work and the production of inositol monophosphate by enzymic hydrolysis of brain phosphoinositides (Rodnight, 1956) led us to study the enzyme responsible in more detail (Kemp et al., 1959, 1961). The phosphoinositidase C identified and partly purified then has proved to be the enzyme involved in receptor-linked metabolism of the inositol lipids. It hydrolyses all three phosphoinositides with the release of diacylglycerol and an inositol phosphate. A major step forward came from Michell (1975), who suggested that the receptors linked with phosphoinositide breakdown also raised intracellular Ca2+ concentration. His theory that Ptdlns was the lipid involved and that its hydrolysis opened Ca2+ channels in the plasma membrane was incorrect, but it stimulated a search for a better explanation. Dureil et al. (1968) had suggested that PtdIns4P might be hydrolysed by cholinergic agonists and AbdelLatif et al. (1977) showed that PtdIns(4,5)P2 of iris muscle was lost in the same way, although this seemed a consequence, not a cause, of Ca'+ influx. Kirk et al. (1981), however, could demonstrate that vasopressin, a Ca2+ mobilizing hormone, caused hydrolysis of polyphosphoinositides in hepatocytes and that ionophore-mediated influx of Ca'+ caused no such hydrolysis. This opened the way for Berridge (1983) to show that inositol 1,4,5-trisphosphate released by hormone-activated hydrolysis of PtdIns(4,5)P2 was a second messenger mobilizing Ca2+ from intracellular st ores.