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J. Biol. Chem., Vol. 282, Issue 41, 29855-29865, October 12, 2007

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Caveolin-1 Regulates the Delivery and Endocytosis of the Glutamate Transporter, Excitatory Amino Acid Carrier 1^*

From the Departments of Pediatrics and Pharmacology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4318

The sodium-dependent glutamate transporter, excitatory amino acid carrier 1 (EAAC1), has been implicated in the regulation of excitatory signaling and prevention of cell death in the nervous system. There is evidence that EAAC1 constitutively cycles on and off the plasma membrane and that under steady state conditions up to 80% of the transporter is intracellular. As is observed with other neurotransmitter transporters, the activity of EAAC1 is regulated by a variety of molecules, and some of these effects are associated with redistribution of EAAC1 on and off the plasma membrane. In the present study we tested the hypothesis that a structural component of lipid rafts, caveolin-1 (Cav-1), may participate in EAAC1 trafficking. Using C6 glioma cells as a model system, co-expression of Cav-1 S80E (a dominant-negative variant) or small interfering RNA-mediated knock-down of caveolin-1 reduced cell surface expression of myc epitope-tagged EAAC1 or endogenous EAAC1, respectively. Cav-1 S80E slowed the constitutive delivery and endocytosis of myc-EAAC1. In primary cultures derived from caveolin-1 knock-out mice, a similar reduction in delivery and internalization of endogenous EAAC1 was observed. We also found that caveolin-1, caveolin-2, or Cav-1 S80E formed immunoprecipitable complexes with EAAC1 in C6 glioma and/or transfected HEK cells. Together, these data provide strong evidence that caveolin-1 contributes to the trafficking of EAAC1 on and off the plasma membrane and that these effects are associated with formation of EAAC1-caveolin complexes.

Received for publication, June 8, 2007 , and in revised form, August 2, 2007.

^* This work was supported in part by National Institutes of Health Grant NS39011 (to M. B. R.). 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 Supported by Postdoctoral Fellowship 0325614U from the American Heart Association.

² To whom correspondence should be addressed: 502N Abramson Pediatric Research Bldg., 3615 Civic Center Blvd., Philadelphia, PA 19104-4318. Tel.: 215-590-2205; Fax: 215-590-3779; E-mail: Robinson{at}pharm.med.upenn.edu.

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