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J. Biol. Chem., Vol. 279, Issue 18, 18840-18850, April 30, 2004

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Hetero-oligomerization between GABA_A and GABA_B Receptors Regulates GABA_B Receptor Trafficking^*

Srividya Balasubramanian, Jeremy A. Teissére, Dinesh V. Raju¶, and Randy A. Hall||

From the Departments of Pharmacology and ^¶Neurology, Emory University School of Medicine, Atlanta, Georgia 30322

The neurotransmitter -aminobutyric acid (GABA) mediates inhibitory signaling in the brain via stimulation of both GABA_A receptors (GABA_AR), which are chloride-permeant ion channels, and GABA_B receptors (GABA_BR), which signal through coupling to G proteins. Here we report physical interactions between these two different classes of GABA receptor. Association of the GABA_B receptor 1 (GABA_BR1) with the GABA_A receptor 2S subunit robustly promotes cell surface expression of GABA_BR1 in the absence of GABA_BR2, a closely related GABA_B receptor that is usually required for efficient trafficking of GABA_BR1 to the cell surface. The GABA_BR1/2S complex is not detectably functional when expressed alone, as assessed in both ERK activation assays and physiological analyses in oocytes. However, the 2S subunit associates not only with GABA_BR1 alone but also with the functional GABA_BR1/GABA_BR2 heterodimer to markedly enhance GABA_B receptor internalization in response to agonist stimulation. These findings reveal that the GABA_BR1/2S interaction results in the regulation of multiple aspects of GABA_B receptor trafficking, allowing for cross-talk between these two distinct classes of GABA receptor.

Received for publication, December 9, 2003 , and in revised form, February 10, 2004.

^* This work was supported by National Institutes of Health Grant R01-NS45644, a Distinguished Young Scholar in Medical Research award from the W. M. Keck Foundation (to R. A. H.), and an NRSA post-doctoral award from the National Institutes of Health (to J. A. T.). 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.

Present address: Dept. of Biology, Muhlenberg College, Allentown, PA 18104.

^|| To whom correspondence should be addressed: Dept. of Pharmacology, Emory University School of Medicine, 5113 Rollins Research Center, 1510 Clifton Rd., Atlanta, GA 30322. Tel.: 404-727-3699; Fax: 404-727-0365; E-mail: rhall{at}pharm.emory.edu.

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