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J. Biol. Chem., Vol. 280, Issue 26, 24420-24427, July 1, 2005

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Phosphorylation-independent Regulation of Metabotropic Glutamate Receptor 1 Signaling Requires G Protein-coupled Receptor Kinase 2 Binding to the Second Intracellular Loop^*

Gurpreet K. Dhami¶, Andy V. Babwah||, Rachel Sterne-Marr**, and Stephen S. G. Ferguson

From the Cell Biology Research Group, Robarts Research Laboratory and Department of Physiology and Pharmacology, The University of Western Ontario, 100 Perth Drive, London, Ontario N6A 5K8, Canada and ^**Biology Department, Siena College, Loudonville, New York 12211

Metabotropic glutamate receptors (mGluRs) are members of a unique class of G protein-coupled receptors (class III) that include the calcium-sensing and -aminobutyric acid type B receptors. The activity of mGluRs is regulated by second messenger-dependent protein kinases and G protein-coupled receptor kinases (GRKs). The attenuation of both mGluR1a and mGluR1b signaling by GRK2 is phosphorylation- and -arrestin-independent and requires the concomitant association of GRK2 with both the receptor and G_q/11. G protein interactions are mediated, in part, by the mGluR1 intracellular second loop, but the domains required for GRK2 binding are unknown. In the present study, we showed that GRK2 binds to the second intracellular loop of mGluR1a and mGluR1b and also to the mGluR1a carboxyl-terminal tail. Alanine scanning mutagenesis revealed a discrete domain within loop 2 that contributes to GRK2 binding, and the mutation of either lysine 691 or 692 to an alanine within this domain resulted in a loss of GRK2 binding to both mGluR1a and mGluR1b. Mutation of either Lys⁶⁹¹ or Lys⁶⁹² prevented GRK2-mediated attenuation of mGluR1b signaling, whereas the mutation of only Lys⁶⁹² prevented GRK2-mediated inhibition of mGluR1a signaling. Thus, the mGluR1a carboxyl-terminal tail may also be involved in regulating the signaling of the mGluR1a splice variant. Taken together, our findings indicated that kinase binding to an mGluR1 domain involved in G protein-coupling is essential for the phosphorylation-independent attenuation of signaling by GRK2.

Received for publication, February 11, 2005 , and in revised form, April 26, 2005.

^* This work was supported in part by Canadian Institutes of Health Research Grant MA-15506 (to S. S. G. F.) and National Science Foundation Grant MCB0315888 (to R. S.-M.). 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.

^¶ Recipient of a Canadian Institutes of Health Research doctoral training award.

^|| Recipient of a Canadian Hypertension Society/Canadian Institutes of Health Research fellowship.

Holds a Canada Research Chair in Molecular Neuroscience, recipient of the Premier's Research Excellence Award, and a Career Investigator of the Heart and Stroke Foundation of Ontario. To whom correspondence should be addressed: Robarts Research Institute, 100 Perth Drive, 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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