Phosphoinositide Contributions To study the roles of phosphoinositides in the plasma membrane of mammalian cells, Hammond et al. (p. 727 , published online 21 June; see the Perspective by Fairn and Grinstein ) engineered phosphatase molecules that could be targeted to the membrane on demand, where they would alter the concentrations of the phospholipids phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P 2 ] and phosphatidylinositol 4-phosphate (PI4P). PI4P was thought to provide a major source for the synthesis of PI(4,5)P 2 , but depletion of PI4P did not have much affect on synthesis of PI(4,5)P 2 . Instead, PI4P appears to help to establish the negative charge at the membrane and thus promote electrostatic interactions with positively charged amino acids in membrane-associated proteins and influencing function of ion channels.