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Molecular and Cellular Biology, December 2000, p. 9356-9363, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Cyclic AMP Promotes Neuronal Survival by Phosphorylation of Glycogen Synthase Kinase 3beta

Mingtao Li,1 Xiaomin Wang,1 Mary Kay Meintzer,1 Tracey Laessig,1 Morris J. Birnbaum,2 and Kim A. Heidenreich1,*

Department of Pharmacology, University of Colorado Health Sciences Center, and The Denver Veterans Affairs Medical Center, Denver, Colorado,1 and The Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania2

Received 10 April 2000/Returned for modification 14 May 2000/Accepted 18 August 2000

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

* Corresponding author. Mailing address: Denver VAMC, 1055 Clermont St., Denver, CO 80220. Phone: (303) 399-8020, ext. 3891. Fax: (303) 393-5271. E-mail: kim.heidenreich{at}uchsc.edu.

Molecular and Cellular Biology, December 2000, p. 9356-9363, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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