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J. Biol. Chem., Vol. 282, Issue 45, 32983-32990, November 9, 2007

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Role of Inositol 1,4,5-Trisphosphate Receptors in Apoptosis in DT40 Lymphocytes^*

From the Department of Pathology and Cell Biology, Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania 19107

The role of inositol 1,4,5-trisphosphate receptors (IP₃R) in caspase-3 activation and cell death was investigated in DT40 chicken B-lymphocytes stably expressing various IP₃R constructs. Both full-length type-I IP₃R and a truncated construct corresponding to the caspase-3 cleaved "channel-only" fragment were able to support staurosporine (STS)-induced caspase-3 activation and cell death even when the IP₃R construct harbored a mutation that inactivates the pore of the Ca²⁺ channel (D2550A). However, a full-length wild-type IP₃R did not promote caspase-3 activation when the 159-amino acid cytosol-exposed C-terminal tail was deleted. STS caused an increase in cytosolic free Ca²⁺ in DT40 cells expressing wild-type or pore-dead IP₃R mutants. However, in the latter case all the Ca²⁺ increase originated from Ca²⁺ entry across the plasma membrane. Caspase-3 activation of pore-dead DT40 cells was also more sensitive to extracellular Ca²⁺ chelation when compared with wild-type cells. STS-mediated release of cytochrome c into the cytosol and mitochondrial membrane potential depolarization could also be observed in DT40 cells lacking IP₃Rs or containing the pore-dead mutant. We conclude that nonfunctional IP₃Rs can sustain apoptosis in DT40 lymphocytes, because they facilitate Ca²⁺ entry mechanisms across the plasma membrane. Although the intrinsic ion-channel function of IP₃Rs is dispensable for apoptosis induced by STS, the C-terminal tail of IP₃Rs appears to be essential, possibly reflecting key protein-protein interactions with this domain.

Received for publication, June 25, 2007 , and in revised form, August 23, 2007.

^* This work was supported by National Institutes of Health Grants R01-DK34804 and R29-NS051822 (to S. K. J.) and Training Grant T32-AA07463 (to Z. T. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Dept. of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust St., JAH 230A, Philadelphia, PA 19107. Tel.: 215-503-1222; Fax: 215-923-6813; E-mail: suresh.joseph{at}mail.tju.edu.

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