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J. Biol. Chem., Vol. 281, Issue 22, 15475-15484, June 2, 2006

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Intracellular Trafficking of KA2 Kainate Receptors Mediated by Interactions with Coatomer Protein Complex I (COPI) and 14-3-3 Chaperone Systems^*

Pornpun Vivithanaporn, Sheng Yan, and Geoffrey T. Swanson¹

From the Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555-1031 and the Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611-3008

Assembly and trafficking of neurotransmitter receptors are processes contingent upon interactions between intracellular chaperone systems and discrete determinants in the receptor proteins. Kainate receptor subunits, which form ionotropic glutamate receptors with diverse roles in the central nervous system, contain a variety of trafficking determinants that promote either membrane expression or intracellular sequestration. In this report, we identify the coatomer protein complex I (COPI) vesicle coat as a critical mechanism for retention of the kainate receptor subunit KA2 in the endoplasmic reticulum. COPI subunits immunoprecipitated with KA2 subunits from both cerebellum and COS-7 cells, and -COP protein interacted directly with immobilized KA2 peptides containing the arginine-rich retention/retrieval determinant. Association between COPI proteins and KA2 subunits was significantly reduced upon alanine substitution of this signal in the cytoplasmic tail of KA2. Temperature-sensitive degradation of COPI complex proteins was correlated with an increase in plasma membrane localization of the homologous KA2 receptor. Assembly of heteromeric GluR6a/KA2 receptors markedly reduced association of KA2 and COPI. Finally, the reduction in COPI binding was correlated with an increased association with 14-3-3 proteins, which mediate forward trafficking of other integral signaling proteins. These interactions therefore represent a critical early checkpoint for biosynthesis of functional KARs.

Received for publication, November 10, 2005 , and in revised form, March 29, 2006.

^* This work was supported by a Young Investigators Award from the National Alliance for Research on Schizophrenia and Depression and NIMH Grant R03 MH65289 (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.

¹ To whom correspondence should be addressed: Northwestern University, Feinberg School of Medicine, Dept. of Molecular Pharmacology and Biological Chemistry, Chicago, IL 60611-3008. Tel.: 312-503-1052; Fax: 312-503-5349; E-mail: gtswanson{at}northwestern.edu.

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