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J. Biol. Chem., Vol. 280, Issue 41, 34840-34848, October 14, 2005

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Inhibition of Metabotropic Glutamate Receptor Signaling by the Huntingtin-binding Protein Optineurin^*

Pieter H. Anborgh, Christina Godin, Macarena Pampillo1, Gurpreet K. Dhami2, Lianne B. Dale, Sean P. Cregan, Ray Truant¶, and Stephen S. G. Ferguson3

From the Cell Biology Research Group, Robarts Research Institute and Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario N6A 5K8, Canada and ^¶Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada

Huntington disease is caused by a polyglutamine expansion in the huntingtin protein (Htt) and is associated with excitotoxic death of striatal neurons. Group I metabotropic glutamate receptors (mGluRs) that are coupled to inositol 1,4,5-triphosphate formation and the release of intracellular Ca²⁺ stores play an important role in regulating neuronal function. We show here that mGluRs interact with the Htt-binding protein optineurin that is also linked to normal pressure open angled glaucoma and, when expressed in HEK 293 cells, optineurin functions to antagonize agonist-stimulated mGluR1a signaling. We find that Htt is co-precipitated with mGluR1a and that mutant Htt functions to facilitate optineurin-mediated attenuation of mGluR1a signaling. In striatal cell lines derived from Htt^Q111/Q111 mutant knock-in mice mGluR5-stimulated inositol phosphate formation is also severely impaired when compared with striatal cells derived from Htt^Q7/Q7 knock-in mice. In addition, we show that a missense single nucleotide polymorphism optineurin H486R variant previously identified to be associated with glaucoma is selectively impaired in mutant Htt binding. Although optineurin H486R retains the capacity to bind to mGluR1a, optineurin H486R-dependent attenuation of mGluR1a signaling is not enhanced by the expression of mutant Htt. Because G protein-coupled receptor kinase 2 (GRK2) protein expression is relatively low in striatal tissue, we propose that optineurin may substitute for GRK2 in the striatum to mediate mGluR desensitization. Taken together, these studies identify a novel mechanism for mGluR desensitization and an additional biochemical link between altered glutamate receptor signaling and Huntington disease.

Received for publication, April 25, 2005 , and in revised form, July 15, 2005.

^* This work was supported by Canadian Institutes of Health Research (CIHR) GrantMA-15506 (to S. S. G. 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 Recipient of a Canadian Hypertension Society/CIHR fellowship.

² Recipient of a CIHR doctoral training award.

³ Holder of a Canada Research Chair in Molecular Neuroscience and a Career Investigator of the Heart and Stroke Foundation of Ontario. To whom correspondence should be addressed: Robarts Research Inst., 100 Perth Dr., P. O. Box 5015, London, Ontario N6A 5K8, Canada. Tel.: 519-663-3825; Fax: 519-663-3314; E-mail: ferguson{at}robarts.ca.

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