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J. Biol. Chem., Vol. 280, Issue 24, 22968-22976, June 17, 2005

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Differential Trafficking of GluR7 Kainate Receptor Subunit Splice Variants^*

Frédéric Jaskolski, Elisabeth Normand, Christophe Mulle, and Françoise Coussen

From the Laboratoire Physiologie Cellulaire de la Synapse, CNRS Unité Mixte de Recherche 5091, Institut François Magendie, Université Bordeaux 2, Rue C. Saint-Saëns, 33077 Bordeaux Cedex, France

Kainate receptors (KARs) are heteromeric ionotropic glutamate receptors that play a variety of roles in the regulation of synaptic network activity. The function of glutamate receptors (GluRs) is highly dependent on their surface density in specific neuronal domains. Alternative splicing is known to regulate surface expression of GluR5 and GluR6 subunits. The KAR subunit GluR7 exists under different splice variant isoforms in the C-terminal domain (GluR7a and GluR7b). Here we have studied the trafficking of GluR7 splice variants in cultured hippocampal neurons from wild-type and KAR mutant mice. We have found that alternative splicing regulates surface expression of GluR7-containing KARs. GluR7a and GluR7b differentially traffic from the ER to the plasma membrane. GluR7a is highly expressed at the plasma membrane, and its trafficking is dependent on a stretch of positively charged amino acids also found in GluR6a. In contrast, GluR7b is detected at the plasma membrane at a low level and retained mostly in the endoplasmic reticulum (ER). The RXR motif of GluR7b does not act as an ER retention motif, at variance with other receptors and ion channels, but might be involved during the assembly process. Like GluR6a, GluR7a promotes surface expression of ER-retained subunit splice variants when assembled in heteromeric KARs. However, our results also suggest that this positive regulation of KAR trafficking is limited by the ability of different combinations of subunits to form heteromeric receptor assemblies. These data further define the complex rules that govern membrane delivery and subcellular distribution of KARs.

Received for publication, November 22, 2004 , and in revised form, March 9, 2005.

^* This work was supported by grants by the Centre National de la Recherche Scientifique, the Ministère de la Recherche of France, and the Conseil Régional d'Aquitaine, as well as by European Commission Contract QLRT-2000-02089. 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.

The on-line version of this article (available at www.jbc.org) contains supplemental material in the form of Figs. sup 1 (biotinylation assay), sup 2 (expression of GluR5–7 subunits in cultured hippocampal neurons), sup 3 (glycosylation state of GluR7a in brain extracts), and sup 4 (BLAST search and ClustalW alignment).

To whom correspondence should be addressed. Tel.: 33-5-5757-4086; Fax: 33-5-5757-4082; E-mail: mulle{at}u-bordeaux2.fr.

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