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J. Biol. Chem., Vol. 278, Issue 52, 52700-52709, December 26, 2003

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Cell Surface Expression of GluR5 Kainate Receptors Is Regulated by an Endoplasmic Reticulum Retention Signal^*

Zhao Ren, Nathan J. Riley, Leigh A. Needleman, James M. Sanders¶, Geoffrey T. Swanson¶, and John Marshall||

From the Department of Molecular Pharmacology, Physiology and Biotechnology and Department of Neuroscience, Brown University, Providence, Rhode Island 02912 and the ^¶Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555

Kainate receptors (KARs) are mediators of excitatory neurotransmission in the mammalian central nervous system, and their efficient targeting and trafficking is critical for normal synaptic function. A key step in the delivery of KARs to the neuronal plasma membrane is the exit of newly assembled receptors from the endoplasmic reticulum (ER). Here we report the identification of a novel ER retention signal in the alternatively spliced C-terminal domain of the GluR5–2b subunit, which controls receptor trafficking in both heterologous cells and neurons. The ER retention motif consists of a critical arginine (Arg-896) and surrounding amino acids, disruption of which promotes ER exit and surface expression of the receptors, as well as altering their physiological properties. The Arg-896-mediated ER retention of GluR5 is regulated by a mutation that mimics phosphorylation of Thr-898, but not by PDZ interactions. Furthermore, two positively charged residues (Arg-900 and Lys-901) in the C terminus were also found to regulate ER export of the receptors. Taken together, our results identify novel trafficking signals in the C-terminal domain of GluR5–2b and demonstrate that alternative splicing is an important mechanism regulating KAR function.

Received for publication, August 28, 2003 , and in revised form, October 3, 2003.

^* This work was supported by Grants NS39309 and NS39063 from the National Institutes of Health (to J. M.), Grant 9940131N from the American Heart Association (to J. M.), Centers of Biomedical Research Excellence (COBRE) Grant RR15578 (to J. M.), a National Institute on Drug Abuse predoctoral award (to J. M. S.), and Grants MH065289 from the National Institute of Mental Health and NS44322 from NINDS, National Institutes of Health (to G. T. S.). 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 Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Box G-B4, Providence, RI 02912. Tel.: 401-863-2574; Fax: 401-863-1595; E-mail: john_marshall{at}brown.edu.

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