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J. Cell Biol. 166 (2): 193-203

Copyright © 2004 by the Rockefeller University Press.

Article

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

Abstract: Inositol 1,4,5-trisphosphate (InsP3) receptors (InsP3Rs) are channels responsible for calcium release from the endoplasmic reticulum (ER). We show that the anti-apoptotic protein Bcl-2 (either wild type or selectively localized to the ER) significantly inhibited InsP3-mediated calcium release and elevation of cytosolic calcium in WEHI7.2 T cells. This inhibition was due to an effect of Bcl-2 at the level of InsP3Rs because responses to both anti-CD3 antibody and a cell-permeant InsP3 ester were decreased. Bcl-2 inhibited the extent of calcium release from the ER of permeabilized WEHI7.2 cells, even at saturating concentrations of InsP3, without decreasing luminal calcium concentration. Furthermore, Bcl-2 reduced the open probability of purified InsP3Rs reconstituted into lipid bilayers. Bcl-2 and InsP3Rs were detected together in macromolecular complexes by coimmunoprecipitation and blue native gel electrophoresis. We suggest that this functional interaction of Bcl-2 with InsP3Rs inhibits InsP3R activation and thereby regulates InsP3-induced calcium release from the ER.

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 hexakisbutyryloxymethyl ester; ICB, intracellular buffer; IL-2, interleukin-2; InsP3, inositol 1,4,5-trisphosphate; InsP3R, InsP3 receptor; TCR, T cell receptor; TG, thapsigargin; TMRE, tetramethylrhodamine ethyl ester.

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