Ca ²⁺ -Induced Apoptosis Through Calcineurin Dephosphorylation of BAD

TLDR

Calcineurin, a Ca²⁺‑activated phosphatase, induces apoptosis but its mechanism was previously unknown. Calcineurin dephosphorylates BAD, leading to its dissociation from 14‑3‑3, mitochondrial translocation, and enhanced heterodimerization with Bcl‑xL, thereby promoting apoptosis—a Ca²⁺‑dependent process observed in hippocampal neurons and suppressible by calcineurin inhibitors.

Abstract

The Ca 2+ -activated protein phosphatase calcineurin induces apoptosis, but the mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-x L and promoting apoptosis. The Ca 2+ -induced dephosphorylation of BAD correlated with its dissociation from 14-3-3 in the cytosol and translocation to mitochondria where Bcl-x L resides. In hippocampal neurons, l -glutamate, an inducer of Ca 2+ influx and calcineurin activation, triggered mitochondrial targeting of BAD and apoptosis, which were both suppressible by coexpression of a dominant-inhibitory mutant of calcineurin or pharmacological inhibitors of this phosphatase. Thus, a Ca 2+ -inducible mechanism for apoptosis induction operates by regulating BAD phosphorylation and localization in cells.