title: Calcium-dependent lateral organization in phosphatidylinositol 4,5-bisphosphate (PIP2)- and cholesterol-containing monolayers.
abstract: Biological membrane function, in part, depends upon the local regulation of lipid composition. The spatial heterogeneity of membrane lipids has been extensively explored in the context of cholesterol and phospholipid acyl-chain-dependent domain formation, but the effects of lipid head groups and soluble factors in lateral lipid organization are less clear. In this contribution, the effects of divalent calcium ions on domain formation in monolayers containing phosphatidylinositol 4,5-bisphosphate (PIP2), a polyanionic, multifunctional lipid of the cytosolic leaflet of the plasma bilayer, are reported. In binary monolayers of PIP2 mixed with zwitterionic lipids, calcium induced a rapid, PIP2-dependent surface pressure drop, with the concomitant formation of laterally segregated, PIP2-rich domains. The effect was dependent upon head-group multivalency, because lowered pH suppressed the surface-pressure effect and domain formation. In accordance with previous observations, inclusion of cholesterol in lipid mixtures induced coexistence of two liquid phases. Phase separation strongly segregated PIP2 to the cholesterol-poor phase, suggesting a role for cholesterol-dependent lipid demixing in regulating PIP2 localization and local concentration. Similar to binary mixtures, subphase calcium induced contraction of ternary cholesterol-containing monolayers; however, in these mixtures, calcium induced an unexpected, PIP2- and multivalency-dependent decrease in the miscibility phase transition surface pressure, resulting in rapid dissolution of the domains. This result emphasizes the likely critical role of subphase factors and lipid head-group specificity in the formation and stability of cholesterol-dependent domains in cellular plasma membranes.
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia,Pennsylvania 19104, USA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Levental
authors.forename: David A
authors.initials: DA
authors.lastname: Christian
authors.forename: Yu-Hsiu
authors.initials: YH
authors.lastname: Wang
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Madara
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Discher
authors.forename: Paul A
authors.initials: PA
authors.lastname: Janmey
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002417:Cattle; D002462:Cell Membrane / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D003600:Cytosol / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011312:Pressure; D015398:Signal Transduction / Q000187:drug effects; D055672:Static Electricity; D013499:Surface Properties / Q000187:drug effects
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D002784:Cholesterol; D002118:Calcium