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J. Biol. Chem., Vol. 281, Issue 25, 17501-17509, June 23, 2006

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A New Motif Necessary and Sufficient for Stable Localization of the 2 Glutamate Receptors at Postsynaptic Spines^*

From the Department of Physiology, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan

The number of each subclass of ionotropic glutamate receptors (iGluRs) at the spines is differentially regulated either constitutively or in a neuronal activity-dependent manner. The 2 glutamate receptor (GluR2) is abundantly expressed at the spines of Purkinje cell dendrites and controls synaptic plasticity in the cerebellum. To obtain clues to the trafficking mechanism of the iGluRs, we expressed wild-type or mutant GluR2 in cultured hippocampal and Purkinje neurons and analyzed their intracellular localization using immunocytochemical techniques. Quantitative analysis revealed that deletion of the 20 amino acids at the center of the C terminus (region E) significantly reduced the amount of GluR2 protein at the spines in both types of neurons. This effect was partially antagonized by the inhibition of endocytosis by high dose sucrose treatment or coexpression of dominant negative dynamin. In addition, mutant GluR2 lacking the E region (GluR2^E), but not wild-type GluR2, was found to colocalize with the endosomal markers Rab4 and Rab7. Moreover, the antibody-feeding assay revealed that GluR2^E was internalized more rapidly than GluR2^wt. These results indicate that the E region (more specifically, a 12-amino-acid-long segment of the E2 region) is necessary for rendering GluR2 resistant to endocytosis from the cell surface at the spines. Furthermore, insertion of the E2 region alone into the C terminus of the GluR1 subtype of iGluRs was sufficient to increase the amount of GluR1 proteins in the spines. Therefore, we propose that the E2 region of GluR2 is necessary, and also sufficient, to inhibit endocytosis of the receptor from postsynaptic membranes.

Received for publication, January 10, 2006 , and in revised form, April 20, 2006.

^* This work was supported by a grant-in-aid for young scientists (to S. M. and K. M.), the Keio Gijuku academic development funds, Keio University grant-in-aid for encouragement of young medical scientists (to S. M.), the grant-in-aid for Scientific Research on Priority Areas, the national grant-in-aid for the establishment of a high tech research center in a private university (to S. M. and M. Y.), the Toray Science and Technology grant, and the Keio University Special grant-in-aid for Innovative Collaborative Research Projects (to M. 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: Dept. of Physiology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: 81-3-5363-3749; Fax: 81-3-3359-0437; E-mail: myuzaki{at}sc.itc.keio.ac.jp.

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