Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate

doi:10.1083/jcb.200309146

Published 19 July 2004. doi:10.1083/jcb.200309146
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 2, 193-203

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Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate

Rui Chen¹, Ignacio Valencia², Fei Zhong¹, Karen S. McColl¹, H. Llewelyn Roderick³, Martin D. Bootman³, Michael J. Berridge³, Stuart J. Conway⁴, Andrew B. Holmes⁴, Gregory A. Mignery⁵, Patricio Velez², and Clark W. Distelhorst¹

¹ Department of Medicine and Department of Pharmacology, Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106
² Center for Cellular and Molecular Neuroscience, Faculty of Sciences, University of Valparaíso, Valparaíso, Chile
³ Laboratory of Molecular Signaling, The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK
⁴ Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK
⁵ Department of Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153

Address correspondence to Clark W. Distelhorst, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4937. Tel.: (216) 368-4546. Fax: (216) 368-1166. email: cwd{at}case.edu

Inositol 1,4,5-trisphosphate (InsP₃) receptors (InsP₃Rs) arechannels responsible for calcium release from the endoplasmicreticulum (ER). We show that the anti-apoptotic protein Bcl-2(either wild type or selectively localized to the ER) significantlyinhibited InsP₃-mediated calcium release and elevation of cytosoliccalcium in WEHI7.2 T cells. This inhibition was due to an effectof Bcl-2 at the level of InsP₃Rs because responses to both anti-CD3antibody and a cell-permeant InsP₃ ester were decreased. Bcl-2inhibited the extent of calcium release from the ER of permeabilizedWEHI7.2 cells, even at saturating concentrations of InsP₃, withoutdecreasing luminal calcium concentration. Furthermore, Bcl-2reduced the open probability of purified InsP₃Rs reconstitutedinto lipid bilayers. Bcl-2 and InsP₃Rs were detected togetherin macromolecular complexes by coimmunoprecipitation and bluenative gel electrophoresis. We suggest that this functionalinteraction of Bcl-2 with InsP₃Rs inhibits InsP₃R activationand thereby regulates InsP₃-induced calcium release from theER.

Key Words: InsP₃ receptor; calcium signaling; apoptosis; calcium channel; T cell receptor

Abbreviations used in this paper: BN-PAGE, blue native–PAGE;ECB, extracellular buffer; D-myo InsP₃BM, D-myo InsP₃ hexakisbutyryloxymethylester; ICB, intracellular buffer; IL-2, interleukin-2; InsP₃,inositol 1,4,5-trisphosphate; InsP₃R, InsP₃ receptor; TCR, Tcell receptor; TG, thapsigargin; TMRE, tetramethylrhodamineethyl ester.

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