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J. Biol. Chem., Vol. 282, Issue 6, 3904-3917, February 9, 2007

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Regulation and Function of Glycogen Synthase Kinase-3 Isoforms in Neuronal Survival^*

From the Molecular Neurobiology Section, National Institute of Mental Health, Bethesda, Maryland 20892-1363

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase consisting of two isoforms, and . The activities of GSK-3 are regulated negatively by serine phosphorylation but positively by tyrosine phosphorylation. GSK-3 inactivation has been proposed as a mechanism to promote neuronal survival. We used GSK-3 isoform-specific small interfering RNAs, dominant-negative mutants, or pharmacological inhibitors to search for functions of the two GSK-3 isoforms in regulating neuronal survival in cultured cortical neurons in response to glutamate insult or during neuronal maturation/aging. Surprisingly, RNA interference-induced depletion of either isoform was sufficient to block glutamate-induced excitotoxicity, and the resulting neuroprotection was associated with enhanced N-terminal serine phosphorylation in both GSK-3 isoforms. However, GSK-3 depletion was more effective than GSK-3 depletion in suppressing spontaneous neuronal death in extended culture. This phenomenon is likely due to selective and robust inhibition of GSK-3 activation resulting from GSK-3 Ser⁹ dephosphorylation during the course of spontaneous neuronal death. GSK-3 silencing resulted in reduced tyrosine phosphorylation of GSK-3, suggesting that tyrosine phosphorylation is also a critical autoregulatory event. Interestingly, GSK-3 inhibitors caused a rapid and long-lasting increase in GSK-3 Ser²¹ phosphorylation levels, followed by a delayed increase in GSK-3 Ser⁹ phosphorylation and a decrease in GSK-3 Tyr²⁷⁹ and GSK-3 Tyr²¹⁶ phosphorylation, thus implying additional levels of GSK-3 autoregulation. Taken together, our results underscore important similarities and dissimilarities of GSK-3 and GSK-3 in the roles of cell survival as well as their distinct modes of regulation. The development of GSK-3 isoform-specific inhibitors seems to be warranted for treating GSK-3-mediated pathology.

Received for publication, May 30, 2006 , and in revised form, December 1, 2006.

^* This work was supported by Intramural Research Program Project Z01MH002468-18 from the National Institute of Mental Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental "Materials and Methods" and Figs. S1–S3.

¹ To whom correspondence should be addressed: NIMH, Bldg. 10, Rm. 4C-206, 10 Center Dr. MSC 1363, Bethesda, MD 20892-1363. Tel.: 301-496-4915; Fax: 301-480-9290; E-mail: chuang{at}mail.nih.gov.

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