Exocytosis: removing the PIPs

Despite their low abundance in biological membranes, phosphoinositides are important cellular regulators. Phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P₂] regulates both endocytosis and exocytosis, but its role in the latter process is unclear. On p. 2084, Giampietro Schiavo and co-workers report that elimination of PtdIns(4,5)P₂ from the plasma membrane is required for regulated exocytosis in activated mast cells. These cells release pro-inflammatory mediators by exocytosis of pre-formed granules, a process that involves granule-plasma-membrane fusion and granule-granule fusion but no compensatory endocytosis. Using quantitative immunofluorescence, the authors show that PtdIns(4,5)P₂ is present in the plasma membrane of mast cells but not their granule membranes. Upon activation of exocytosis, they report, PtdIns(4,5)P₂ is transiently depleted from the plasma membrane by phosphatidylinositol-specific phospholipase C; both removal of PtdIns(4,5)P₂ and production of its metabolite diacylglycerol (but not activation of Ca²⁺ signalling,) are required for exocytosis. The authors conclude that a cycle of PtdIns(4,5)P₂ synthesis and breakdown regulates exocytosis in mast cells and speculate that a similar cycle functions in other secretory cells.