Requirement of biphasic calcium release from the endoplasmic reticulum for Fas-mediated apoptosis.
Fas receptor is a member of the tumor necrosis factor-alpha family of death receptors that mediate physiologic apoptotic signaling. To investigate the molecular mechanisms regulating calcium mobilization during Fas-mediated apoptosis, we have analyzed the sequential steps leading to altered calcium homeostasis and cell death in response to activation of the Fas receptor. We show that Fas-mediated apoptosis requires endoplasmic reticulum-mediated calcium release in a mechanism dependent on phospholipase C-gamma1 (PLC-gamma1) activation and Ca2+ release from inositol 1,4,5-trisphosphate receptor (IP3R) channels. The kinetics of Ca2+ release were biphasic, demonstrating a rapid elevation caused by PLC-gamma1 activation and a delayed and sustained increase caused by cytochrome c binding to IP3R. Blocking either phase of Ca2+ mobilization was cytoprotective, highlighting PLC-gamma1 and IP3R as possible therapeutic targets for disorders associated with Fas signaling.
Wozniak
Ann L
AL
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Wang
Xinmin
X
Stieren
Emily S
ES
Scarbrough
Shelby G
SG
Elferink
Cornelis J
CJ
Boehning
Darren
D
D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism / Q000502:physiology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D051966:Phospholipase C gamma / Q000378:metabolism*; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology*
D053222:Fas Ligand Protein; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019014:fas Receptor; D045304:Cytochromes c; D051966:Phospholipase C gamma; D002118:Calcium