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J. Biol. Chem. 277 (28): 25266-25272

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Phosphorylation-independent Regulation of Metabotropic Glutamate Receptor Signaling by G Protein-coupled Receptor Kinase 2*

Gurpreet Kaur DhamiDagger §, Pieter H. AnborghDagger , Lianne B. DaleDagger , Rachel Sterne-Marr, and Stephen S. G. FergusonDagger §||**Dagger Dagger

From the Dagger  Cell Biology Research Group, the John P. Robarts Research Institute, Departments of § Pharmacology and Toxicology, || Physiology, and ** Medicine, University of Western Ontario, Ontario N6A 5K8, Canada and the  Biology Department, Siena College, Loudonville, New York 12211

The accepted paradigm for G protein-coupled receptor kinase (GRK)-mediated desensitization of G protein-coupled receptors involves GRK-mediated receptor phosphorylation followed by the binding of arrestin proteins. Although GRKs contribute to metabotropic glutamate receptor 1 (mGluR1) inactivation, beta -arrestins do not appear to be required for mGluR1 G protein uncoupling. Therefore, we investigated whether the phosphorylation of serine and threonine residues localized within the C terminus of mGluR1a is sufficient to allow GRK2-mediated attenuation of mGluR1a signaling. We find that the truncation of the mGluR1a C-terminal tail prevents mGluR1a phosphorylation and that GRK2 does not contribute to the phosphorylation of an mGluR1 splice variant (mGluR1b). However, mGluR1a-866Delta - and mGluR1b-stimulated inositol phosphate formation is attenuated following GRK2 expression. The expression of the GRK2 C-terminal domain to block membrane translocation of endogenous GRK2 increases mGluR1a-866Delta - and mGluR1b-stimulated inositol phosphate formation, presumably by blocking membrane translocation of GRK2. In contrast, expression of the kinase-deficient GRK2-K220R mutant inhibits inositol phosphate formation by these unphosphorylated receptors. Expression of the GRK2 N-terminal domain (residues 45-185) also attenuates both constitutive and agonist-stimulated mGluR1a, mGluR1a-866Delta , and mGluR1b signaling, and the GRK2 N terminus co-precipitates with mGluR1a. Taken together, our observations indicate that attenuation of mGluR1 signaling by GRK2 is phosphorylation-independent and that the interaction of the N-terminal domain of GRK2 with mGluR1 contributes to the regulation of mGluR1 G protein coupling.

* This work was supported by Canadian Institutes of Health Research Grant MA-15506 (to S. S. G. F.), National Science Foundation Grant MCB9728179 (to R. S. M.), and funds from the Southeastern Pennsylvania Affiliate of the American Heart Association (to R. S. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Dagger Recipient of a McDonald Scholarship from the Heart and Stroke Foundation of Canada, the Premier's Research Excellence Award, and the Canada Research Chair in Molecular Neuroscience. To whom correspondence should be addressed: Robarts Research Inst., 100 Perth Dr., P.O. Box 5015, London, ON N6A 5K8, Canada. Tel.: 519-663-3825; Fax: 519-663-3789; E-mail: ferguson@rri.ca.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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