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J. Biol. Chem., Vol. 283, Issue 10, 6561-6571, March 7, 2008

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Reticulon RTN2B Regulates Trafficking and Function of Neuronal Glutamate Transporter EAAC1^*

Yiting Liu, Svetlana Vidensky, Alicia M. Ruggiero¹, Susanne Maier, Harald H. Sitte, and Jeffrey D. Rothstein^¶2

From the Departments of Neurology and ^¶Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21287 and the Institute of Pharmacology, Center for Biomolecular Medicine and Pharmacology, Medical University of Vienna, Waehringerstrasse 13a, A-1090 Vienna, Austria

Excitatory amino acid transporters (EAATs) are the primary regulators of extracellular glutamate concentrations in the central nervous system. Their dysfunction may contribute to several neurological diseases. To date, five distinct mammalian glutamate transporters have been cloned. In brain, EAAC1 (excitatory amino acid carrier 1) is the primary neuronal glutamate transporter, localized on the perisynaptic membranes that are near release sites. Despite its potential importance in synaptic actions, little is known concerning the regulation of EAAC1 trafficking from the endoplasmic reticulum (ER) to the cell surface. Previously, we identified an EAAC1-associated protein, GTRAP3-18, an ER protein that prevents ER exit of EAAC1 when induced. Here we show that RTN2B, a member of the reticulon protein family that mainly localizes in the ER and ER exit sites interacts with EAAC1 and GTRAP3-18. EAAC1 and GTRAP3-18 bind to different regions of RTN2B. Each protein can separately and independently form complexes with EAAC1. RTN2B enhances ER exit and the cell surface composition of EAAC1 in heterologous cells. Expression of short interfering RNA-mediated knockdown of RTN2B decreases the EAAC1 protein level in neurons. Overall, our results suggest that RTN2B functions as a positive regulator in the delivery of EAAC1 from the ER to the cell surface. These studies indicate that transporter exit from the ER controlled by the interaction with its ER binding partner represents a critical regulatory step in glutamate transporter trafficking to the cell surface.

Received for publication, September 28, 2007 , and in revised form, December 10, 2007.

^* This work was supported by National Institutes of Health Grants NS33958, NS40151, and NS52179 (to J. D. R.) and Austrian Science Foundation/FWF Grants P17076 [GenBank] and 18706 (to H. H. 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 Present address: Dept. of Pharmacology, Center for Molecular Neuroscience, Vanderbilt University, 465 21st Ave., Nashville, TN 37232.

² To whom correspondence should be addressed: Dept. of Neurology, Meyer 6-109, 600 N. Wolfe St., Baltimore, MD 21287. Tel.: 410-614-3846; Fax: 410-955-0672; E-mail: jrothstein{at}jhmi.edu.

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