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J. Biol. Chem., Vol. 280, Issue 39, 33566-33572, September 30, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/39/33566    most recent M503482200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sauter, K. Articles by Benke, D. Search for Related Content PubMed PubMed Citation Articles by Sauter, K. Articles by Benke, D. Social Bookmarking                      What's this?

Subtype-selective Interaction with the Transcription Factor CCAAT/Enhancer-binding Protein (C/EBP) Homologous Protein (CHOP) Regulates Cell Surface Expression of GABA_B Receptors^*

Kathrin Sauter, Thomas Grampp, Jean-Marc Fritschy, Klemens Kaupmann, Bernhard Bettler¶, Hanns Mohler||, and Dietmar Benke1

From the Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, the ^||Department of Chemistry and Applied Biosciences, Federal Institute of Technology (ETH), 8093 Zurich, Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4002 Basel, and the ^¶Pharmazentrum, University of Basel, Department of Clinical-Biological Sciences, Institute of Physiology, 4056 Basel, Switzerland

The metabotropic -aminobutyric acid, type B (GABA_B) receptors mediate the slow component of GABAergic transmission in the brain. Functional GABA_B receptors are heterodimers of the two subunits GABA_B1 and GABA_B2, of which GABA_B1 exists in two main isoforms, GABA_B1a and GABA_B1b. The significance of the structural heterogeneity of GABA_B receptors, the mechanism leading to their differential targeting in neurons as well as the regulation of cell surface numbers of GABA_B receptors, is poorly understood. To gain insights into these processes, we searched for proteins interacting with the C-terminal domain of GABA_B2. Here, we showed that the transcription factor CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) directly interacts with GABA_B receptors in a subtype-selective manner to regulate cell surface expression of GABA_B1a/GABA_B2 receptors upon co-expression in HEK 293 cells. The interaction of CHOP with GABA_B1a/GABA_B2 receptors resulted in their intracellular accumulation and in a reduced number of cell surface receptors. This regulation required the interaction of CHOP via two distinct domains with the heterodimeric receptor; its C-terminal leucine zipper associates with the leucine zipper present in the C-terminal domain of GABA_B2, and its N-terminal domain associates with an as yet unidentified site on GABA_B1a. In conclusion, the data indicated a subtype-selective regulation of cell surface receptors by interaction with the transcription factor CHOP.

Received for publication, March 30, 2005 , and in revised form, July 26, 2005.

^* 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: Institute of Pharmacology and Toxicology, University Zürich, Winterthurerstrasse.190, 8057 Zürich. Tel.: 41-44-635-5930; Fax: 41-44-635-6874; E-mail: benke{at}pharma.unizh.ch.

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