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J. Biol. Chem., Vol. 280, Issue 23, 22044-22052, June 10, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/23/22044    most recent M413987200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, Y.-I. Articles by Juhnn, Y.-S. Search for Related Content PubMed PubMed Citation Articles by Lee, Y.-I. Articles by Juhnn, Y.-S. Social Bookmarking                      What's this?

Membrane Depolarization Induces the Undulating Phosphorylation/Dephosphorylation of Glycogen Synthase Kinase 3, and This Dephosphorylation Involves Protein Phosphatases 2A and 2B in SH-SY5Y Human Neuroblastoma Cells^*

Yun-Il Lee, MiRan Seo, Yeni Kim, So-Young Kim, Ung Gu Kang, Yong-Sik Kim, and Yong-Sung Juhnn¶

From the Department of Biochemistry and Department of Psychiatry, Seoul National University College of Medicine, Seoul 110-799, Korea

Changes in plasma membrane electrical potential evoke signals that regulate the expressions of various genes in the nervous system. However, the role of glycogen synthase kinase 3 (GSK-3) in this process has not been elucidated. Thus, this study was performed to examine whether membrane depolarization can regulate the phosphorylation of GSK-3 and to identify the molecular mechanisms involved in this regulation. The depolarization by treating with 100 mM KCl for 5 min resulted in the undulating phosphorylation of GSK-3 at Ser-9 in SH-SY5Y human neuroblastoma cells, in H19 –7/IGF-IR rat embryonic hippocampal cells, and in PC12 rat pheochromocytoma cells, but not in A172 human glioblastoma cells. Cellular -catenin contents showed a temporal pattern similar to that of the Ser-9 phosphorylation of GSK-3. Treatment with wortmannin or calphostin C or the expression of dominant negative Akt inhibited phosphorylation of GSK-3 at Ser-9 following the KCl-induced depolarization of SH-SY5Y cells. Moreover, pretreatment with okadaic acid or cyclosporin A blocked the dephosphorylation of GSK-3 at Ser-9 at 0, 15, and 30 min after KCl-induced depolarization, and the activity of protein phosphatases (PP) 2A and 2B increased at these times. Treatment with nifedipine or calcium-free medium inhibited GSK-3 dephosphorylation following membrane depolarization, and the amounts of co-immunoprecipitated GSK-3 and PP2A changed in parallel with GSK-3 dephosphorylation. Our study demonstrated that KCl-induced depolarization caused undulating GSK-3 phosphorylation/dephosphorylation, which was regulated for the most part by phosphatidylinositol 3-kinase and Akt (phosphorylation) and PP2A and PP2B (dephosphorylation), respectively.

Received for publication, December 13, 2004 , and in revised form, March 25, 2005.

^* This work was supported by Grant R01-2002-000-00144-0 from the basic research program of the Korea Science and Engineering Foundation, by Grant M1-0108-00-0082 from the Korean Ministry of Science and Technology, by Grant 03-2002-020 from the Seoul National University Hospital Research Fund, and by the 2004 BK21 Project for Medicine, Dentistry, and Pharmacy. 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.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Republic of Korea. Tel.: 82-2-740-8247; Fax: 82-2-744-4534; E-mail: juhnn{at}snu.ac.kr.

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