Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3 beta

Agents that elevate intracellular cyclic AMP (cAMP) levels promote neuronal survival in a manner independent of neurotrophic factors. Inhibitors of ph osphatidylinositol 3 kinase and dominant-inactive mutants of the protein ki nase Akt do not block the survival effects of cAMP, suggesting that another signaling pathway is involved. In this report, we demonstrate that elevati on of intracellular cAMP levels in mt cerebellar granule neurons leads to p hosphorylation and inhibition of glycogen synthase kinase 3 beta (GSK-3 bet a). The increased phosphorylation of GSK-3 beta by protein kinase A (PKA) o ccurs at serine 9, the same site phosphorylated by Akt. Purified PKA is abl e to phosphorylate recombinant GSK-3 beta in vitro. Inhibitors of GSK-3 blo ck apoptosis in these neurons, and transfection of neurons with a GSK-3 bet a mutant that cannot be phosphorylated interferes with the prosurvival effe cts of cAMP. These data suggest that activated PKA directly phosphorylates GSK-3 beta and inhibits its apoptotic activity in neurons.