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J. Biol. Chem., Vol. 278, Issue 35, 33105-33119, August 29, 2003

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Gene Structure of the Human Metabotropic Glutamate Receptor 5 and Functional Analysis of Its Multiple Promoters in Neuroblastoma and Astroglioma Cells^*

Corrado Corti  , Richard W. E. Clarkson ¶, Luca Crepaldi  ||, Cinzia F. Sala , John H. Xuereb  and Francesco Ferraguti  || **

From the Cambridge Brain Bank Laboratory, Department of Pathology, University of Cambridge, Level 3 Laboratory Block Addenbrooke's Hospital, Hills Road, CB2 2QQ Cambridge, the ^¶Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QP Cambridge, United Kingdom, the ^||Department of Pharmacology, University of Innsbruck, Peter Mayr Strasse 1a, A-6020 Innsbruck, Austria, and the Department of Biology, Psychiatry Centre of Excellence in Drug Discovery, GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy

The metabotropic glutamate receptor 5 (mGluR5) has a discrete tissue expression mainly limited to neural cells. Expression of mGluR5 is developmentally regulated and undergoes dramatic changes in association with neuropathological disorders. We report the complete genomic structure of the mGluR5 gene, which is composed of 11 exons and encompasses 563 kbp. Three clusters of multiple transcription initiation sites located on three distinct exons (IA, IB, and II), which undergo alternative splicing, have been identified. The 5'-flanking regions of these exons were isolated and, using a luciferase reporter gene assay, shown to possess active promoter elements in SKN-MC neuroblastoma and U178-MG astroglioma cells. Promoter IA was characterized by a CpG island; promoter IB contained a TATA box, and promoter II possessed three active Oct-1-binding sites. Preferential luciferase activity was observed in SKN-MC concomitant with differential DNA binding activity to several responsive elements, including CREB, Oct-1, C/EBP, and Brn-2. Exposure to growth factors produced enhanced expression of promoters IB and II in astroglioma cells and activation of NF-B. These results suggest that alternative 5'-splicing and usage of multiple promoters may contribute regulatory mechanisms for tissue- and context-specific expression of the mGluR5 gene.

Received for publication, December 5, 2002 , and in revised form, May 9, 2003.

^* 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.

^** To whom correspondence should be addressed: Dept. of Pharmacology, University of Innsbruck, Peter Mayr Strasse 1a, A-6020 Innsbruck, Austria. Tel.: 43-512-507-3704; Fax: 43-512-507-2783; E-mail: francesco.ferraguti{at}uibk.ac.at.

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				L. Crepaldi, C. Lackner, C. Corti, and F. Ferraguti Transcriptional Activators and Repressors for the Neuron-specific Expression of a Metabotropic Glutamate Receptor J. Biol. Chem., June 15, 2007; 282(24): 17877 - 17889. [Abstract] [Full Text] [PDF]