Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival

Bcl-2 interacts with the inositol 1,4,5-trisphosphate receptor (InsP(3)R) and thus prevents InsP(3)-induced Ca2+ elevation that induces apoptosis. Here we report that Bcl-2 binds dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a protein kinase A (PKA)-activated and calcineurin (CaN)-deactivated inhibitor of protein phosphatase 1 (PP1). Bcl-2 docks DARPP-32 and CaN in a complex on the InsP3R, creating a negative feedback loop that prevents exaggerated Ca2+ release by decreasing PKA-mediated InsP(3)R phosphorylation. T-cell activation increases PKAactivity, phosphorylating both the InsP(3)R and DARPP-32. Phosphorylated DARPP-32 inhibits PP1, enhancing InsP(3)R phosphorylation and Ca2+ release. Elevated Ca2+ activates CaN, which dephosphorylates DARPP-32 to dampen Ca2+ release by eliminating PP1 inhibition to enable it to dephosphorylate the InsP(3)R. Knocking down either Bcl-2 orDARPP-32abrogates this feedbackmechanism, resulting inincreased Ca2+ elevation and apoptosis. This feedback mechanism appears to be exploited by high levels of Bcl-2 in chronic lymphocytic leukemia cells, repressing B-cell receptor-induced Ca2+ elevation and apoptosis.