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J. Biol. Chem., Vol. 283, Issue 36, 24641-24648, September 5, 2008

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The Availability of Surface GABA_B Receptors Is Independent of -Aminobutyric Acid but Controlled by Glutamate in Central Neurons^*

Karina J. Vargas¹², Miho Terunuma^¶13, Judith A. Tello, Menelas N. Pangalos^||, Stephen J. Moss^¶**, and Andrés Couve, Supported by FONDECYT 1071001 and Iniciativa Científica Milenio ICM-P04-068-F⁴

From the Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile, Universidad Austral de Chile, Independencia 567, Valdivia, Chile, the ^¶Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, ^||Wyeth Research, Neuroscience Discovery, Princeton, New Jersey 08543, and the ^**Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom

The efficacy of synaptic transmission depends on the availability of ionotropic and metabotropic neurotransmitter receptors at the plasma membrane, but the contribution of the endocytic and recycling pathways in the regulation of -aminobutyric acid type B (GABA_B) receptors remains controversial. To understand the mechanisms that regulate the abundance of GABA_B receptors, we have studied their turnover combining surface biotin labeling and a microscopic immunoendocytosis assay in hippocampal and cortical neurons. We report that internalization of GABA_B receptors is agonist-independent. We also demonstrate that receptors endocytose in the cell body and dendrites but not in axons. Additionally, we show that GABA_B receptors endocytose as heterodimers via clathrin- and dynamin-1-dependent mechanisms and that they recycle to the plasma membrane after endocytosis. More importantly, we show that glutamate decreases the levels of cell surface receptors in a manner dependent on an intact proteasome pathway. These observations indicate that glutamate and not GABA controls the abundance of surface GABA_B receptors in central neurons, consistent with their enrichment at glutamatergic synapses.

Received for publication, March 27, 2008 , and in revised form, June 4, 2008.

^* 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 Figs. 1 and 2.

¹ Both authors contributed equally to this work.

² Supported by Ph.D. Fellowships D-21050545 and 24071048 from CONICYT.

³ Supported by the American Heart Association.

⁴ To whom correspondence should be addressed: Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile. Tel.: 56-2-978-6878; Fax: 56-2-777-6916; E-mail: andres{at}neuro.med.uchile.cl.

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