title: Regulation of the transbilayer movement of diacylglycerol in the plasma membrane.
abstract: This mini-review presents recent advances in the regulation of the membrane transbilayer movement (or flip-flop) of diacylglycerol (DAG), a key intermediate in lipid metabolism and a second messenger in lipid-mediated signaling. Despite progresses in lipid biophysics and imaging, little is known about the DAG dynamics across the two leaflets of the plasma membrane in living cells. Previous model membrane studies with DAG analogs demonstrated their fast flip-flop suggesting that DAG is evenly distributed between the two leaflets of the plasma membrane. However, recent molecular dynamics simulations indicate that DAG transbilayer movement depends on the lipid environment surrounding the lipid, i.e. DAG flips more slowly across a more ordered "lipid raft-like" bilayer (enriched in sphingomyelin/cholesterol) than across a more fluid bilayer (composed of unsaturated glycerophospholipids). Furthermore using the yellow fluorescent protein-tagged C1AB domain from protein kinase C-γ (EYFP-C1AB) that selectively binds DAG, we recently proved that the sphingomyelin (SM) content in the plasma membrane outer leaflet regulates DAG transbilayer movement in Madin-Darby canine kidney cells treated with bacterial phosphatidylcholine-specific phospholipase C. The dose-dependent inhibition of DAG flip-flop by SM could be reproduced in model membranes using fluorescent short chain DAG analog. Regulation of DAG transbilayer movement by the outer leaflet SM content is expected to modify the downstream recruitment of C1-domain containing effectors, thus bringing new insights on the role of DAG dynamics in cell pathophysiology.
authors.affiliation: Lipid Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan. Electronic address: yueda@kanazawa-med.ac.jp.
authors.forename: Yoshibumi
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Lipid Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan. Electronic address: isitsuka@riken.jp.
authors.forename: Reiko
authors.initials: R
authors.lastname: Ishitsuka
authors.affiliation: Lipid Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan; Inserm U1060, Université Lyon 1, 69621 Villeurbanne, France. Electronic address: hullin-matsuda@riken.jp.
authors.forename: Françoise
authors.initials: F
authors.lastname: Hullin-Matsuda
authors.affiliation: Lipid Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan; Inserm U1060, Université Lyon 1, 69621 Villeurbanne, France. Electronic address: kobayasi@riken.jp.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D004075:Diglycerides / Q000737:chemistry / Q000378:metabolism*; D004285:Dogs; D031541:Fluorescence Resonance Energy Transfer; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008856:Microscopy, Fluorescence; D013109:Sphingomyelins / Q000737:chemistry / Q000378:metabolism*
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; D008051:Lipid Bilayers; D013109:Sphingomyelins
keywords: C1AB domain; Diacylglycerol; Flip-flop; Lipid probe; Sphingomyelin