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J. Biol. Chem., Vol. 278, Issue 35, 33364-33369, August 29, 2003

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Expression of Polyglutamine-expanded Huntingtin Induces Tyrosine Phosphorylation of N-Methyl-D-aspartate Receptors^*

Cheng Song , Yuntian Zhang , Chris G. Parsons  and Ya Fang Liu  ¶

From the Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118 and the Department of Pharmacology, Merz and Company, Eckenheimer Landstrasse 100-104, Frankfurt am Main D-60318, Germany

In our previous studies, we found that expression of polyglutamine-expanded huntingtin in HN33 cells induced sensitization of N-methyl-D-aspartate (NMDA) receptors (Sun, Y., Savinainen, A., and Liu, Y. F. (2001) J. Biol. Chem. 276, 24713–24718). Following this study, we investigated whether tyrosine phosphorylation of NMDA receptors might contribute to the altered property of the receptors. Expression of polyglutamine-expanded huntingtin induced elevation of phosphorylated or activated Src and increased targeting of PSD-95 (post-synaptic density 95) and activated Src to cell surface membrane. Expression of the mutated huntingtin also induced tyrosine phosphorylation of NR2B (NMDA receptor 2B) subunits, and co-expression of PSD-95 enhanced the phosphorylation. Treatment of SU6656 (a specific Src inhibitor) or co-expression of a mutated NR2B subunit with mutations of all three major tyrosine phosphorylation sites significantly attenuated neuronal toxicity induced by the mutated huntingtin. Addition of AP-5 did not further inhibit the neuronal toxicity. Taken together, our studies show that polyglutamine-expanded huntingtin increases tyrosine phosphorylation of NMDA receptors via PSD-95 and Src, and increased tyrosine phosphorylation may contribute to the sensitization of the receptors mediated by polyglutamine-expanded huntingtin.

Received for publication, April 23, 2003 , and in revised form, June 13, 2003.

^* This work was supported by The United States Army Medical Research and Materiel Command under Cooperative Agreement DAMD17-00-2-0012 (to Y. F. L.). 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 Pharmacology, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Tel.: 617-638-4593; Fax: 617-638-5650; E-mail: yafliu{at}bu.edu.

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