High level calcineurin activity predisposes neuronal cells to apoptosis

Calcineurin is a Ca2+/calmodulin-dependent protein phosphatase that is abun dantly expressed in several specific areas of the brain, which are exceptio nally vulnerable to stroke, epilepsy, and neurodegenerative diseases. In th is study, we assessed the effects of high level activity of calcineurin on neuronal cells. Virus-mediated high level constitutive activity of calcineu rin rendered neuronal cells susceptible to apoptosis induced by serum reduc tion or by a brief exposure to calcium ionophore. Adenovirus-mediated, high level forced activity of calcineurin induced cytochrome c/caspase-3-depend ent apoptosis in neurons. Preincubation with the calcineurin inhibitors cyc losporin A and FK506 reduced susceptibility to apoptosis. High level consti tutive expression of Bcl-2 or CrmA or incubation with a specific caspase-3 inhibitor inhibited the calcineurin-induced apoptosis. These data indicate that high level constitutive activity of calcineurin predisposes neuronal c ells to cytochrome c/caspase-3 dependent apoptosis even under sublethal con ditions.