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J. Biol. Chem., Vol. 280, Issue 7, 6085-6093, February 18, 2005

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Ligand Binding Is a Critical Requirement for Plasma Membrane Expression of Heteromeric Kainate Receptors^*

Lokanatha Valluru, Jian Xu, Yongling Zhu, Sheng Yan, Anis Contractor¶, and Geoffrey T. Swanson||

From the Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555-1031, the Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California 92037, and the ^¶Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611

Intracellular trafficking of ionotropic glutamate receptors is controlled by multiple discrete determinants in receptor subunits. Most such determinants have been localized to the cytoplasmic carboxyl-terminal domain, but other domains in the subunit proteins can play roles in modulating receptor surface expression. Here we demonstrate that formation of an intact glutamate binding site also acts as an additional quality-control check for surface expression of homomeric and heteromeric kainate receptors. A key ligand-binding residue in the KA2 subunit, threonine 675, was mutated to either alanine or glutamate, which eliminated affinity for the receptor ligands kainate and glutamate. We found that plasma membrane expression of heteromeric GluR6/KA2(T675A) or GluR6/KA2(T675E) kainate receptors was markedly reduced compared with wild-type GluR6/KA2 receptors in transfected HEK 293 and COS-7 cells and in cultured neurons. Surface expression of homomeric KA2 receptors lacking a retention/retrieval determinant (KA2-R/A) was also reduced upon mutation of Thr-675 and elimination of the ligand binding site. KA2 Thr-675 mutant subunits were able to co-assemble with GluR5 and GluR6 subunits and were degraded at the same rate as wild-type KA2 subunit protein. These results suggest that glutamate binding and associated conformational changes are prerequisites for forward trafficking of intracellular kainate receptors following multimeric assembly.

Received for publication, October 12, 2004 , and in revised form, December 1, 2004.

^* This work was supported by NIMH Grant R03-MH065289 and NINDS, National Institutes of Health (NIH) Grant R01-NS44322 (to G. T. S.) and by NIMH Grant R03-MH65632 (to A. C.). The support of the National Institute of Environmental Health Sciences, NIH Center and the Optical Imaging Laboratory at University of Texas Medical Branch is also appreciated. 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 and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1031. Tel.: 409-772-9653; Fax: 409-772-9642; E-mail: g.swanson{at}utmb.edu.

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