Specific lipids supply critical negative spontaneous curvature--an essential component of native Ca2+-triggered membrane fusion |
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Authors: | Churchward Matthew A Rogasevskaia Tatiana Brandman David M Khosravani Houman Nava Phillip Atkinson Jeffrey K Coorssen Jens R |
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Affiliation: | * Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1 † Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada T2N 4N1 ‡ Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, Canada T2N 4N1 § Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1 ¶ Department of Chemistry, Brock University, St. Catharines, Ontario, Canada L2S 3A1 |
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Abstract: | The Ca2+-triggered merger of two apposed membranes is the defining step of regulated exocytosis. CHOL is required at critical levels in secretory vesicle membranes to enable efficient, native membrane fusion: CHOL-sphingomyelin enriched microdomains organize the site and regulate fusion efficiency, and CHOL directly supports the capacity for membrane merger by virtue of its negative spontaneous curvature. Specific, structurally dissimilar lipids substitute for CHOL in supporting the ability of vesicles to fuse: diacylglycerol, αT, and phosphatidylethanolamine support triggered fusion in CHOL-depleted vesicles, and this correlates quantitatively with the amount of curvature each imparts to the membrane. Lipids of lesser negative curvature than cholesterol do not support fusion. The fundamental mechanism of regulated bilayer merger requires not only a defined amount of membrane-negative curvature, but this curvature must be provided by molecules having a specific, critical spontaneous curvature. Such a local lipid composition is energetically favorable, ensuring the necessary “spontaneous” lipid rearrangements that must occur during native membrane fusion—Ca2+-triggered fusion pore formation and expansion. Thus, different fusion sites or vesicle types can use specific alternate lipidic components, or combinations thereof, to facilitate and modulate the fusion pore. |
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Keywords: | CHOL, cholesterol DOPE, dioleoylphosphatidylethanolamine αT, α-tocopherol DOG, dioleoylglycerol DOPC, dioleoylphosphatidylcholine DOPA, dioleoylphosphatidic acid Me-DOPE, N-methyl dioleoylphosphatidylethanolamine Me2-DOPE, N,N-dimethyl dioleoylphosphatidylethanolamine CV, cortical vesicles CHOL-B, cholesteryl BODIPY FL-C12 DiI, 1,1&prime -dioctadecyl-3,3,3&prime ,3&prime -tetramethylindocarbocyanine perchlorate PLD, phospholipase D PM, plasma membrane HPTLC, high-performance thin layer chromatography BIM, baseline intracellular media DMSO, dimethylsulfoxide C9NBD-T, C9-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-tocopherol mß cd, methyl-β-cyclodextrin hpß cd, hydroxypropyl-β-cyclodextrin LPC, lysophosphatidylcholine PA, phosphatidic acid |
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