title: Maintenance and regulation of asymmetric phospholipid distribution in human erythrocyte membranes: implications for erythrocyte functions.
abstract: OBJECTIVE
  The article summarizes new insights into the molecular mechanisms for the maintenance and regulation of the asymmetric distribution of phospholipids in human erythrocyte membranes. We focus on phosphatidylserine, which is primarily found in the inner leaflet of the membrane lipid bilayer under low Ca conditions (<1 μmol/l) and is exposed to the outer leaflet under elevated Ca concentrations (>1 μmol/l), when cells become senescent. Clarification of the molecular basis of phosphatidylserine flipping and scrambling is important for addressing long-standing questions regarding phosphatidylserine functions.
  
  
  RESULTS
  ATP11C, a P-IV ATPase, has been identified as a major flippase in analyses of patient erythrocytes with a 90% reduction in flippase activity. Phospholipid scramblase 1 (PLSCR1) has been defined as a Ca-activated scramblase that is completely suppressed by membrane cholesterol under low Ca concentrations.
  
  
  CONCLUSIONS
  For survival, phosphatidylserine surface exposure is prevented by cholesterol-mediated suppression of PLSCR1 under low Ca concentrations, irrespective of flipping by ATP11C. In senescent erythrocytes, PLSCR1 is activated by elevated Ca, resulting in phosphatidylserine exposure, allowing macrophage phagocytosis. These recent molecular findings establish the importance of the maintenance and regulation of phosphatidylserine distribution for both the survival and death of human erythrocytes.
authors.affiliation: Department of Biochemistry, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Nobuto
authors.initials: N
authors.lastname: Arashiki
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takakuwa
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D001692:Biological Transport; D004910:Erythrocyte Membrane / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D013997:Time Factors
chemical_list: D008563:Membrane Lipids; D026901:Membrane Transport Proteins; C493422:PLSCR1 protein, human; D010718:Phosphatidylserines; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; C000588974:ATP11C protein, human; D000251:Adenosine Triphosphatases