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 relea se 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 signa ling via the T-cell receptor (TCR) (T. Jayaraman, E. Ondriasova, K. On drias, 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 t o apoptosis induced by dexamethasone, TCR stimulation, ionizing radiat ion, and Fas. Resistance to TCR-mediated apoptosis in IP3R1-deficient cells is reversed by pharmacologically raising cytoplasmic calcium lev els. TCR-mediated apoptosis can be induced in calcium-free media, indi cating that extracellular calcium influx is not required. These findin gs suggest that intracellular calcium release via the IP3R1 is a criti cal mediator of apoptosis.