QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.108.052316v1 75/4/991    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services 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 Iacovelli, L. Articles by Nicoletti, F. Search for Related Content PubMed PubMed Citation Articles by Iacovelli, L. Articles by Nicoletti, F.

Regulation of Group II Metabotropic Glutamate Receptors by G Protein-Coupled Receptor Kinases: mGlu2 Receptors Are Resistant to Homologous Desensitization

Departments of Physiology and Pharmacology (L.I., M.M., M.A., F.M., V.B., F.N.) and Experimental Medicine (A.D.B.), University of Rome Sapienza, Rome, Italy; I.N.M. Neuromed, Pozzilli, Italy (G.M., G.B., L.D.M., V.B., F.N.); Institute of Experimental Medicine, Czech Academy of Science, Prague, Czech Republic (J.B.); and Department of Biology, Psychiatry Centre of Excellence in Drug Discovery, GlaxoSmithKline Medicines Research Centre, Verona, Italy (M.C., C.C.)

We examined the regulation of mGlu2 and mGlu3 metabotropic glutamate receptor signaling prompted by the emerging role of these receptor subtypes as therapeutic targets for psychiatric disorders, such as anxiety and schizophrenia. In transfected human embryonic kidney 293 cells, G-protein-coupled receptor kinase (GRK) 2 and GRK3 fully desensitized the agonist-dependent inhibition of cAMP formation mediated by mGlu3 receptors. In contrast, GRK2 or other GRKs did not desensitize the cAMP response to mGlu2 receptor activation. Desensitization of mGlu3 receptors by GRK2 required an intact kinase activity, as shown by the use of the kinase-dead mutant GRK2-K220R or the recombinant GRK2 C-terminal domain. Overexpression of β-arrestin1 also desensitized mGlu3 receptors and did not affect the cAMP signaling mediated by mGlu2 receptors. The difference in the regulation of mGlu2 and mGlu3 receptors was signal-dependent because GRK2 desensitized the activation of the mitogen-activated protein kinase pathway mediated by both mGlu2 and mGlu3 receptors. In vivo studies confirmed the resistance of mGlu2 receptor-mediated cAMP signaling to homologous desensitization. Wild-type, mGlu2(-/-), or mGlu3(-/-) mice were treated intraperitoneally with saline or the mixed mGlu2/3 receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0]-exhane-4,6-dicarboxylic acid (LY379268; 1 mg/kg) once daily for 7 days. Inhibition of forskolin-stimulated cAMP formation by LY379268 was measured in cortical slices prepared 24 h after the last injection. Agonist pretreatment fully desensitized the cAMP response in wild-type and mGlu2(-/-) mice but had no effect in mGlu3(-/-) mice, in which LY379268 could only activate the mGlu2 receptor. We predict the lack of tolerance when mixed mGlu2/3 receptor agonists or selective mGlu2 enhancers are used continually in patients.

Received for publication October 2, 2008.

Accepted for publication January 22, 2009.

Address correspondence to: Dr. Ferdinando Nicoletti, Department of Physiology and Pharmacology, University of Rome Sapienza, Piazzale Aldo Moro, 5, 00185 Rome, Italy. E-mail: ferdinandonicoletti{at}hotmail.com

This article has been cited by other articles:

				B. Wroblewska and D. A. Lewis Validating Novel Targets for Pharmacological Interventions in Schizophrenia Am J Psychiatry, July 1, 2009; 166(7): 753 - 756. [Full Text] [PDF]

				S. Chiechio, M. Zammataro, M. E. Morales, C. L. Busceti, F. Drago, R. W. Gereau IV, A. Copani, and F. Nicoletti Epigenetic Modulation of mGlu2 Receptors by Histone Deacetylase Inhibitors in the Treatment of Inflammatory Pain Mol. Pharmacol., May 1, 2009; 75(5): 1014 - 1020. [Abstract] [Full Text] [PDF]