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

Inositol 1,4,5-trisphosphate (InsP(3)) receptors (InsP(3)Rs) 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 InsP(3)-mediated calcium release and elevation of cytosolic calcium in WEH17.2 T cells. This inhibition was due to an effect of Bcl-2 at the level of InsP(3)Rs because responses to both anti-CD3 antibody and a cell-permeant InsP(3) ester were decreased. Bcl-2 inhibited the extent of calcium release from the ER of permeabilized WEH17.2 cells, even at saturating concentrations of InsP(3), without decreasing luminal calcium concentration. Furthermore, Bcl-2 reduced the open probability of purified InsP(3)Rs reconstituted into lipid bilayers. Bcl-2 and InsP(3)Rs were detected together in macromolecular complexes by coimmunoprecipitation and blue native gel electrophoresis. We suggest that this functional interaction of Bcl-2 with InsP(3)Rs inhibits InsP(3)R activation and thereby regulates InsP(3)-induced calcium release from the ER.