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Originally published In Press as doi:10.1074/jbc.M707238200 on April 3, 2008

J. Biol. Chem., Vol. 283, Issue 22, 15469-15478, May 30, 2008
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Differential Modulation of Akt/Glycogen Synthase Kinase-3β Pathway Regulates Apoptotic and Cytoprotective Signaling Responses*Formula

Venugopalan D. Nair1 and C. Warren Olanow

From the Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029

We have previously reported that specific dopamine agonists mediate protection against apoptosis induced by oxidative stress by activating the D2 receptor-coupled phosphoinositide 3-kinase (PI-3K)/Akt pathway. In the present study we examined the downstream effectors of PI-3K/Akt signaling and their role in cell death after oxidative stress and protection provided by ropinirole, a D2 receptor agonist in PC12 cells and primary cultures of dopamine neurons. Ropinirole treatment was associated with rapid translocation and phosphorylation of the PI-3K substrate Akt and phosphorylation of Akt substrates. One of these Akt downstream substrates was identified as the pro-apoptotic factor glycogen synthase kinase-3β (GSK-3β). Ropinirole-induced protection was associated with phosphorylation of GSK-3β (inactivation). In contrast, inhibition of PI-3K blocked the phosphorylation of Akt and GSK-3β (activation) and prevented the protection mediated by ropinirole. Suppression of Akt with specific short hairpin RNA in normal PC12 cells caused cell death, which was associated with reduced phosphorylation of GSK-3β and reduced levels of β-catenin, a transcriptional activator that is regulated by GSK-3β. Knock-out of GSK-3β expression with a short hairpin RNA alone was itself sufficient to cause cell death. We further demonstrated that oxidative stress induced by hydrogen peroxide (H2O2) dephosphorylates Akt and GSK-3β, increases GSK-3β activity, and promotes an interaction with β-catenin and its degradation. Inhibition of GSK-3β activity by inhibitor VIII protects cells from H2O2 similar to ropinirole. These results indicate that GSK-3β downstream of Akt plays a critical role in cell death and survival in these models.


Received for publication, August 29, 2007 , and in revised form, March 10, 2008.

* This study was supported in part by a grant from GlaxoSmithKline Inc. 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.

Formula The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

1 To whom correspondence should be addressed: Neurology, Box 1137, Mount Sinai School of Medicine, One Gustave L. Levy Place, NY, NY 10029. Tel.: 212-241-5809; Fax: 212-289-4107; E-mail: venugopalan.nair{at}mssm.edu.


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