Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD

The Ca2+-activated protein phosphatase calcineurin induces apoptosis, but t he mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pr o-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerizati on with Bcl-x(L) and promoting apoptosis. The Ca2+-induced dephosphorylatio n of BAD correlated with its dissociation from 14-3-3 in the cytosol and tr anslocation to mitochondria where Bcl-x(L) resides. In hippocampal neurons, L-glutamate, an inducer of Ca2+ influx and calcineurin activation, trigger ed mitochondrial targeting of BAD and apoptosis, which were both suppressib le by coexpression of a dominant-inhibitory mutant of calcineurin or pharma cological inhibitors of this phosphatase. Thus, a Ca2+-inducible mechanism for apoptosis induction operates by regulating BAD phosphorylation and Loca lization in cells.