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Published online 27 November 2006. doi:10.1083/jcb.200608035
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 5, 709-714
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Requirement of biphasic calcium release from the endoplasmic reticulum for Fas-mediated apoptosis



Ann L. Wozniak1, Xinmin Wang1, Emily S. Stieren1, Shelby G. Scarbrough2, Cornelis J. Elferink2, and Darren Boehning1

1 Department of Neuroscience and Cell Biology and 2 Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555

Correspondence to Darren Boehning: dfboehni{at}utmb.edu

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-{gamma}1 (PLC-{gamma}1) 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-{gamma}1 activation and a delayed and sustained increase caused by cytochrome c binding to IP3R. Blocking either phase of Ca2+ mobilization was cytoprotective, highlighting PLC-{gamma}1 and IP3R as possible therapeutic targets for disorders associated with Fas signaling.

Abbreviations used in this paper: DISC, death-induced signaling complex; IP3, inositol 1,4,5-trisphosphate; IP3R, IP3 receptor.


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