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


ABSTRACT: Bcl-2 interacts with the inositol 1,4,5-trisphosphate receptor (InsP3R) and thus prevents InsP3-induced Ca(2+) 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 Ca(2+) release by decreasing PKA-mediated InsP3R phosphorylation. T-cell activation increases PKA activity, phosphorylating both the InsP3R and DARPP-32. Phosphorylated DARPP-32 inhibits PP1, enhancing InsP3R phosphorylation and Ca(2+) release. Elevated Ca(2+) activates CaN, which dephosphorylates DARPP-32 to dampen Ca(2+) release by eliminating PP1 inhibition to enable it to dephosphorylate the InsP3R. Knocking down either Bcl-2 or DARPP-32 abrogates this feedback mechanism, resulting in increased Ca(2+) 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 Ca(2+) elevation and apoptosis.

SUBMITTER: Chang MJ 

PROVIDER: S-EPMC3903247 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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

Chang Ming-Jin MJ   Zhong Fei F   Lavik Andrew R AR   Parys Jan B JB   Berridge Michael J MJ   Distelhorst Clark W CW  

Proceedings of the National Academy of Sciences of the United States of America 20140106 3


Bcl-2 interacts with the inositol 1,4,5-trisphosphate receptor (InsP3R) and thus prevents InsP3-induced Ca(2+) 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 Ca(2+) release by decreasing  ...[more]

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