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J. Biol. Chem., Vol. 282, Issue 6, 4162-4171, February 9, 2007

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GABA_B Receptor Association with the PDZ Scaffold Mupp1 Alters Receptor Stability and Function^*

From the Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322

-Aminobutyric acid, type B (GABA_B) receptors are heterodimeric G protein-coupled receptors that mediate slow inhibitory synaptic transmission in the central nervous system. To identify novel interacting partners that might regulate GABA_B receptor (GABA_BR) functionality, we screened the GABA_BR2 carboxyl terminus against a recently created proteomic array of 96 distinct PDZ (PSD-95/Dlg/ZO-1 homology) domains. The screen identified three specific PDZ domains that exhibit interactions with GABA_BR2: Mupp1 PDZ13, PAPIN PDZ1, and Erbin PDZ. Biochemical analysis confirmed that full-length Mupp1 and PAPIN interact with GABA_BR2 in cells. Disruption of the GABA_BR2 interaction with PDZ scaffolds by a point mutation to the carboxyl terminus of the receptor dramatically decreased receptor stability and attenuated the duration of GABA_B receptor signaling. The effects of mutating the GABA_BR2 carboxyl terminus on receptor stability and signaling were mimicked by small interference RNA knockdown of endogenous Mupp1. These findings reveal that GABA_B receptor stability and signaling can be modulated via GABA_BR2 interactions with the PDZ scaffold protein Mupp1, which may contribute to cell-specific regulation of GABA_B receptors in the central nervous system.

Received for publication, August 11, 2006 , and in revised form, November 6, 2006.

^* This work was supported by National Institutes of Health Grant NS45644 (to R. A. H.), a Distinguished Young Scholar in Medical Research award from the W. M. Keck Foundation (to R. A. H.), an American Heart Association Predoctoral Fellowship (to S. B.), and a Canadian Institutes of Health Research Postdoctoral Fellowship (to S. R. 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.

¹ 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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