T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis.
The type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) calcium release channel is present on the endoplasmic reticulum of most cell types. T lymphocytes which have been made deficient in IP3R1 lack detectable IP3-induced intracellular calcium release and exhibit defective signaling via the T-cell receptor (TCR) (T. Jayaraman, E. Ondriasova, K. Ondrias, D. Harnick, and A. R. Marks, Proc. Natl. Acad. Sci. USA 92:6007-6011, 1995). We now show that IP3R1-deficient T cells are resistant to apoptosis induced by dexamethasone, TCR stimulation, ionizing radiation, and Fas. Resistance to TCR-mediated apoptosis in IP3R1-deficient cells is reversed by pharmacologically raising cytoplasmic calcium levels. TCR-mediated apoptosis can be induced in calcium-free media, indicating that extracellular calcium influx is not required. These findings suggest that intracellular calcium release via the IP3R1 is a critical mediator of apoptosis.
Jayaraman
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Molecular Cardiology Program, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Marks
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AR
D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000172:deficiency*; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019169:Jurkat Cells; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000737:chemistry / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
D015220:Calcium Channels; D002614:Chelating Agents; D004791:Enzyme Inhibitors; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D011948:Receptors, Antigen, T-Cell; D018160:Receptors, Cytoplasmic and Nuclear; D019014:fas Receptor; D004533:Egtazic Acid; D019284:Thapsigargin; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium