Significance The B-cell lymphoma-2 (Bcl-2) protein binds to the inositol 1,4,5-trisphosphate receptor (InsP ₃ R), a ubiquitous intracellular Ca ²⁺ channel, thereby promoting cell survival by preventing excessive Ca ²⁺ elevation. We report here that this mechanism involves Bcl-2 interaction with the Ca ²⁺ -activated protein phosphatase calcineurin (CaN) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a CaN-regulated inhibitor of protein phosphatase 1. Our findings indicate that this complex constitutes a rapid negative feedback mechanism that is activated by Ca ²⁺ elevation and decreases InsP ₃ R phosphorylation, thus inhibiting InsP ₃ R-mediated Ca ²⁺ release. We posit that Bcl-2-overexpressing cancer cells may exploit this mechanism to inhibit apoptosis.