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J. Biol. Chem., Vol. 280, Issue 45, 37526-37535, November 11, 2005

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A Positive Feedback Loop between Glycogen Synthase Kinase 3 and Protein Phosphatase 1 after Stimulation of NR2B NMDA Receptors in Forebrain Neurons^*

Erzsebet Szatmari, Agata Habas, Peng Yang, Jing-Juan Zheng, Theo Hagg, and Michal Hetman¶1

From the Kentucky Spinal Cord Injury Research Center and the Departments of Neurological Surgery and Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40292 and the ^¶Nencki Institute, Pasteura 3, 02-093 Warszawa, Poland

N-methyl-D-aspartate receptors (NMDARs) are critical for neuronal plasticity and survival, whereas their excessive activation produces excitotoxicity and may accelerate neurodegeneration. Here, we report that stimulation of NMDARs in cultured rat hippocampal or cortical neurons and in the adult mouse brain in vivo disinhibited glycogen synthase kinase 3 (GSK3) by protein phosphatase 1(PP1)-mediated dephosphorylation of GSK3 at the serine 9 residue. NMDA-triggered GSK3 activation was mediated by NMDAR that contained the NR2B subunit. Interestingly, GSK3 inhibition reduced inhibitory phosphorylation of the PP1 inhibitor 2 (I2) and attenuated serine 9 dephosphorylation by PP1. These data suggest existence of a feedback loop between GSK3 and PP1 that results in amplification of PP1 activation by GSK3. In addition, GSK3 inhibition decreased PP1-mediated dephosphorylation of the cAMP-response element-binding protein (CREB) at the serine 133 residue in NMDA-stimulated neurons. Conversely, overexpression of GSK3 abolished non-NR2B-mediated activation of CRE-driven transcription. These data suggest that cross-talk between GSK3 and PP1 contributes to NR2B NMDAR-induced inhibition of CREB signaling by non-NR2B NMDAR. The excessive activation of NR2B-PP1-GSK3-PP1 circuitry may contribute to the deficits of CREB-dependent neuronal plasticity in neurodegenerative diseases.

Received for publication, March 11, 2005 , and in revised form, August 19, 2005.

^* This work was supported by National Institutes of Health Grants P20-RR15576 andNS047341-01 (to M. H.), Alzheimer Association Grant IIRG-04-1139 (to M. H.), by the Commonwealth of Kentucky Challenge for Excellence (to M. H. and T. H.), Norton Healthcare (to M. H. and T. H.), and the fellowships from the Kentucky Spinal Cord and Head Injury Research Trust (to E. S. and P. Y.). 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.

¹ To whom correspondence should be addressed: KY Spinal Cord Injury Research Center, University of Louisville, 511 S. Floyd St., MDR616, Louisville, KY 40292. Tel.: 502-852-3619; Fax: 502-852-5148; E-mail: michal.hetman{at}louisville.edu.

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