CALCINEURIN AND MITOCHONDRIAL-FUNCTION IN GLUTAMATE-INDUCED NEURONAL CELL-DEATH

We have previously reported that glutamate can trigger a succession of necrosis and apoptosis in cerebellar granule cells (CGC), Since speci fic blockers of the N-methyl-D-aspartate (NMDA) receptor channel preve nted both types of cell death, the role of Ca2+-dependent processes in the initiation of glutamate toxicity,vas further investigated. We exa mined the possible involvement of mitochondria and the role of the Ca2 +/calmodulin-regulated protein phosphatase, calcineurin, in the develo pment of either type of cell death, Cyclosporin A and the more selecti ve calcineurin inhibitor, PK-506, prevented the development of both ea rly necrosis and delayed apoptosis, In addition, cyclosporin A prevent ed the collapse of mitochondrial membrane potential observed during th e exposure to glutamate and the concomitant necrotic phase, When CsA w as added immediately after glutamate removal, it also prevented delaye d apoptosis of neurons that had survived the necrotic phase, Altogethe r, these results suggest the involvement of calcineurin and a role for mitochondrial deenergization as early signals in neuronal apoptosis i nduced by glutamate.