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PI4P and PI(4,5)P2 Are Essential But Independent Lipid Determinants of Membrane Identity

Science  10 Aug 2012:
Vol. 337, Issue 6095, pp. 727-730
DOI: 10.1126/science.1222483

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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)P2] and phosphatidylinositol 4-phosphate (PI4P). PI4P was thought to provide a major source for the synthesis of PI(4,5)P2, but depletion of PI4P did not have much affect on synthesis of PI(4,5)P2. 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.

Abstract

The quantitatively minor phospholipid phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] fulfills many cellular functions in the plasma membrane (PM), whereas its synthetic precursor, phosphatidylinositol 4-phosphate (PI4P), has no assigned PM roles apart from PI(4,5)P2 synthesis. We used a combination of pharmacological and chemical genetic approaches to probe the function of PM PI4P, most of which was not required for the synthesis or functions of PI(4,5)P2. However, depletion of both lipids was required to prevent PM targeting of proteins that interact with acidic lipids or activation of the transient receptor potential vanilloid 1 cation channel. Therefore, PI4P contributes to the pool of polyanionic lipids that define plasma membrane identity and to some functions previously attributed specifically to PI(4,5)P2, which may be fulfilled by a more general polyanionic lipid requirement.

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