Inositol lipids and phosphates in growing, stimulated and differentiating cells.

Receptor-stimulated phosphatidylinositol (Ptdlns) metabolism was discovered by Hokin & Hokin in 1953 and substantially characterized by the same workers during the following few years (see Hawthorne, 1960). However, the function of this response remained obscure until Michell (1975) realized that it might in some way be responsible for the receptor-stimulated elevation in the cytoplasmic concentration of CaZ+ that is a major intracellular trigger to the physiological responses of target cells, from rapid contraction or secretion through to the initiation of cell proliferation. In 1979, Nishizuka and co-workers discovered that 1,2diacylglycerol released during receptor-activated inositol lipid hydrolysis could serve as a second messenger activating protein kinase C, an observation that transformed inositol lipid hydrolysis into a signalling reaction responsible for the generation of at least two intracellular signals (Nishizuka, 1984). Finally, during the period from 1981 to 1984, it was recognized that phosphatidylinositol 4,s-bisphosphate [PtdIns(4,S)Pz] is the major or only lipid hydrolysed as a direct result of receptor stimulation (Michell et a/., 1981) and that the inositol 1,4,S-trisphosphate [Ins( 1,4,5)P,] liberated by this reaction causes the release of Caz+ from an intracellular pool into the cytosol (Berridge & Irvine, 1984). Thus, in 1984, we briefly had the luxury of the satisfying and tidy conclusion that many receptors cause the activation of phosphoinositidase-C-catalysed Ptdlns(4,S)P2 hydrolysis, directly yielding two cellular messengers [ 1, 2-diacylglycerol and lns(1,4,5)P3] and indirectly causing an increase in the cytosolic concentration of a third (the Ca2+ ion) (reviewed in Downes & Michell, 1985; Nishizuka, 1986; Berridge, 1987; Berridge & Michell, 1988).