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J. Biol. Chem., Vol. 280, Issue 22, 21588-21593, June 3, 2005

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Regulation of N-Methyl-D-aspartate Receptors by Calpain in Cortical Neurons^*

Hai-Yan Wu¶, Eunice Y. Yuen||, Yun-Fei Lu**, Masayuki Matsushita, Hideki Matsui**, Zhen Yan||, and Kazuhito Tomizawa

From the Department of Physiology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan, ^||Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214, and ^**Protein Therapy, New Techno-Venture Oriented R&D, Japan Science and Technology Corporation, Okayama 700-8558, Japan

The N-methyl-D-aspartate (NMDA) receptor is a cation channel highly permeable to calcium and plays critical roles in governing normal and pathologic functions in neurons. Calcium entry through NMDA receptors (NMDARs) can lead to the activation of the Ca²⁺-dependent protease, calpain. Here we investigated the involvement of calpain in regulation of NMDAR channel function. After prolonged (5-min) treatment with NMDA or glutamate, the whole-cell NMDAR-mediated current was significantly reduced in both acutely dissociated and cultured cortical pyramidal neurons. The down-regulation of NMDAR current was blocked by bath application of selective calpain inhibitors. Intracellular injection of a specific calpain inhibitory peptide also eliminated the down-regulation of NMDAR current induced by prolonged NMDA treatment. In contrast, dynamin inhibitory peptide had no effect on the depression of NMDAR current, suggesting the lack of involvement of dynamin/clathrin-mediated NMDAR internalization in this process. Immunoblotting analysis showed that the NR2A and NR2B subunits of NMDARs were markedly degraded in cultured cortical neurons treated with glutamate, and the degradation of NR2 subunits was prevented by calpain inhibitors. Taken together, our results suggest that prolonged activation of NMDARs in neurons activates calpain, and activated calpain in turn down-regulates the function of NMDARs, which provides a neuroprotective mechanism against NMDAR overstimulation accompanying ischemia and stroke.

Received for publication, February 11, 2005 , and in revised form, March 23, 2005.

^* This work was supported by funds from the Industrial Technology Research Grant Program in 2002 from the New Energy and Industrial Technology Development Organization of Japan (to K. T.); a grant-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture of Japan (to K. T. and H. M.); and National Institutes of Health Grant MH63128 and National Science Foundation Grant IBN-0117026 (to Z. 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.

Both authors contributed equally to this work.

^¶ Present address: Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19102.

To whom correspondence should be addressed: Dept. of Physiology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata, Okayama 700-8558, Japan. Tel.: 81-86-235-7109; Fax: 81-86-235–7111; E-mail: tomikt{at}md.okayama-u.ac.jp.

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