Ca 2+ -Induced Apoptosis Through Calcineurin Dephosphorylation of BAD

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.