title: Participation of leukotriene C(4) in the regulation of suicidal erythrocyte death.
abstract: Eryptosis, the suicidal death of erythrocytes, is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. Eryptosis is triggered by increase in cytosolic Ca(2+) concentration upon energy depletion. The present study explored the involvement of leukotrienes. Western blotting was employed to detect the cysteinyl-leukotriene receptor cysLT1, competitive immune assay to determine leukotriene release from erythrocytes, Fluo3 fluorescence to estimate cytosolic Ca(2+) concentration, forward scatter to analyse cell volume and annexin V-binding to disclose phosphatidylserine exposure. As a result, erythrocytes expressed the leukotriene receptor CysLT1. Glucose depletion (24 hours) significantly increased the formation of the cysteinyl-leukotrienes C(4)/D(4)/E(4). Leukotriene C(4) (10 nM) increased Ca(2+) entry, decreased forward scatter, activated caspases 3 and 8, and stimulated annexin V-binding. Glucose depletion similarly increased annexin V-binding, an effect significantly blunted in the presence of the leukotriene receptor antagonist cinalukast (1 microM) or the 5-lipoxygenase inhibitor BW B70C (1 microM). In conclusion, upon energy depletion erythrocytes form leukotrienes, which in turn activate cation channels, leading to Ca(2+) entry, cell shrinkage and cell membrane scrambling. Cysteinyl-leukotrienes thus participate in the signaling of eryptosis during energy depletion.
authors.affiliation: Department of Physiology, University of Tubingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Foller
authors.forename: H
authors.initials: H
authors.lastname: Mahmud
authors.forename: S
authors.initials: S
authors.lastname: Gu
authors.forename: K
authors.initials: K
authors.lastname: Wang
authors.forename: E
authors.initials: E
authors.lastname: Floride
authors.forename: Y
authors.initials: Y
authors.lastname: Kucherenko
authors.forename: S
authors.initials: S
authors.lastname: Luik
authors.forename: S
authors.initials: S
authors.lastname: Laufer
authors.forename: F
authors.initials: F
authors.lastname: Lang
mesh_terms: D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D018613:Microscopy, Confocal; D010718:Phosphatidylserines / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000096:biosynthesis*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D010718:Phosphatidylserines; D018077:Receptors, Leukotriene; D013844:Thiazoles; C080871:BW B70C; D017997:Leukotriene C4; C071436:cinalukast; D053148:Caspase 3; D053181:Caspase 8; D005947:Glucose; C083169:leukotriene D4 receptor; D002118:Calcium; D006918:Hydroxyurea