HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 22, 15469-15478, May 30, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/22/15469    most recent M707238200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Nair, V. D. Articles by Olanow, C. W. PubMed PubMed Citation Articles by Nair, V. D. Articles by Olanow, C. W. Social Bookmarking                      What's this?

Differential Modulation of Akt/Glycogen Synthase Kinase-3β Pathway Regulates Apoptotic and Cytoprotective Signaling Responses^*

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.

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?