title: Stimulation of Erythrocyte Cell Membrane Scrambling by Quinine.
abstract: OBJECTIVE
  The analkaloid drug quinine is utilized mainly for the chemoprophylaxis of malaria. The multiple side effects of quinine include hemolytic anemia and hemolytic uremic syndrome, disorders involving suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling contributing to stimulation of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide and D4476 sensitive casein kinase. The present study explored the putative effect of quinine on eryptosis and elucidated cellular mechanisms involved.
  
  
  METHODS
  Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCF dependent fluorescence, and ceramide abundance utilizing specific antibodies.
  
  
  RESULTS
  A 48 hours exposure of human erythrocytes to quinine (≥ 50 µM) significantly increased the percentage of annexin-V-binding cells without significantly affecting forward scatter. Quinine significantly increased Fluo3-fluorescence, DCF fluorescence and ceramide abundance. The effect of quinine on annexin-V-binding was significantly blunted by removal of extracellular Ca2+ and by addition of D4476 (10 µM).
  
  
  CONCLUSIONS
  Quinine triggers phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca2+ entry, oxidative stress, ceramide and D4476 sensitive casein kinase.
authors.affiliation: Department of Cardiology, Vascular Medicine and Physiology, Eberhard-Karls-University of Tuebingen, Tuebingen, Germany.
authors.forename: Morena
authors.initials: M
authors.lastname: Mischitelli
authors.forename: Mohamed
authors.initials: M
authors.lastname: Jemaà
authors.forename: Mustafa
authors.initials: M
authors.lastname: Almasry
authors.forename: Caterina
authors.initials: C
authors.lastname: Faggio
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D002118:Calcium / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D010718:Phosphatidylserines / Q000378:metabolism; D011803:Quinine / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002518:Ceramides; D010718:Phosphatidylserines; D017382:Reactive Oxygen Species; D011803:Quinine; D002118:Calcium