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J. Biol. Chem., Vol. 283, Issue 10, 6175-6183, March 7, 2008

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The Endoplasmic Reticulum Exit of Glutamate Transporter Is Regulated by the Inducible Mammalian Yip6b/GTRAP3-18 Protein^*

Alicia M. Ruggiero¹, Yiting Liu, Svetlana Vidensky, Susanne Maier^¶, Elizabeth Jung, Hesso Farhan^¶, Michael B. Robinson^||, Harald H. Sitte^¶, and Jeffrey D. Rothstein²

From the Departments of Neuroscience and Neurology, Johns Hopkins University, Baltimore, Maryland 21287, the ^¶Institute of Pharmacology, Center for Biomolecular Medicine and Pharmacology, Medical University of Vienna, Waehringerstrasse 13a, A-1090Vienna and the ^||Departments of Pharmacology and Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104

GTRAP3-18 interacts with and reduces the activity of the neuronal specific Na⁺/K⁺ glutamate transporter, EAAC1 both in vitro and in vivo. GTRAP3-18 and the related isoform, JM4, are distant relatives of the Rab GTPase-interacting factor PRA1, and share a topology of four transmembrane domains and cytosolic termini. GTRAP3-18 and JM4 are resident endoplasmic reticulum (ER) proteins. The physiological role of GTRAP3-18 is poorly understood. We demonstrate for the first time that GTRAP3-18 is a regulator of ER protein trafficking. Expression of GTRAP3-18 delays the ER exit of EAAC1, as well as other members of the excitatory amino acid transporter family. GTRAP3-18 uses hydrophobic domain interactions in the ER membrane to self-associate and cytoplasmic interactions at the C terminus to regulate trafficking. The features of GTRAP3-18 activity are consistent with recent phylogenic sequence analyses suggesting GTRAP3-18 and JM4 be reclassified as mammalian isoforms of the yeast protein family Yip, Yip6b, and Yip6a, respectively.

Received for publication, February 2, 2007 , and in revised form, December 28, 2007.

^* This work was supported in part by National Institutes of Health NS40151 (to J. D. R.), NS36465 (to J. D. R. and M. B. R.), Austrian Science Foundation/FWF 17076 (to H. H. S.), P18076 [GenBank] (to S. M.), and Austrian National Bank 10507 (to H. F.). 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 http://www.jbc.org) contains supplemental Fig. S1.

¹ Present address: Vanderbilt University, Dept. of Pharmacology, Center for Molecular Neuroscience, 465 21st Ave., Nashville, TN 37232.

² To whom correspondence should be addressed: Dept. of Neurology, Johns Hopkins University, Meyer 6-109, 625 N. Wolfe St., Baltimore, MD 21287. Tel.: 410-614-3846; Fax: 410-955-0672; E-mail: jrothstein{at}jhmi.edu.

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