The enormous versatility of phosphatidylinositol as a mediator of intracellular signalling is due to its variable phosphorylation on every combination of the 3′, 4′ and 5′ positions, as well as an even more complex range of phosphorylated products when inositol phosphate is released by phospholipase C activity. The phosphoinositides are produced by distinct enzymes in distinct intracellular membranes, and recruit and regulate downstream signalling proteins containing binding domains [PH (pleckstrin homology), PX (Phox homology), FYVE etc.] that are relatively specific for these lipids. Specific recruitment of downstream proteins presumably involves a coincidence detection mechanism, in which a combination of lipid–protein and protein–protein interactions define specificity. Of the seven intrucellular phosphoinositide, quantification of PtdIns5P levels in intact cells has remained difficult. In this issue of the Biochemical Journal, Sarkes and Rameh describe a novel HPLC-based approach which makes possible an analysis of the subcellular distribution of PtdIns5P and other phosphoinositides.

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