Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

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

L. Iacovelli, G. Molinaro, G. Battaglia, M. Motolese, L. Di Menna, M. Alfiero, J. Blahos, F. Matrisciano, M. Corsi, C. Corti, V. Bruno, A. De Blasi and F. Nicoletti
Molecular Pharmacology April 2009, 75 (4) 991-1003; DOI: https://doi.org/10.1124/mol.108.052316
L. Iacovelli
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
G. Molinaro
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
G. Battaglia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M. Motolese
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
L. Di Menna
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M. Alfiero
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. Blahos
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
F. Matrisciano
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M. Corsi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
C. Corti
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
V. Bruno
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
A. De Blasi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
F. Nicoletti
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

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.

Footnotes

  • This work was funded by the Italian Ministero dell'Istruzione, dell'Università e della Ricerca [Grant PRIN 200728AA57].

  • D.B.A. and N.F. contributed equally to this work.

  • ABBREVIATIONS: mGlu, metabotropic glutamate receptor; GPCR, G-protein-coupled receptor; GRK, G protein-coupled receptor kinase; FSK, forskolin; MAPK, mitogen activated protein kinases; (2R,4R)-APDC, (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate; LY379268(-)-2-oxa-4-aminobicyclo[3.1.0]exhane-4,6-dicarboxylic acid; GRK2-K220R, kinase-dead G protein-coupled receptor kinase 2 mutant; GRK2-Cter, C-terminal domain of G protein-coupled receptor kinase 2; HEK, human embryonic kidney; ERK, extracellular signal-regulated kinase; PTX, pertussis toxin; PH, pleckstrin homology; wt, wild type; ANOVA, analysis of variance; LY354740, (+)-(1S,2S,5R,6S)-2-aminobicyclo(3.1.0)hexane-2,6-dicarboxylic acid; LY404039, 4-amino-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid.

    • Received October 2, 2008.
    • Accepted January 22, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 75 (4)
Molecular Pharmacology
Vol. 75, Issue 4
1 Apr 2009
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Regulation of Group II Metabotropic Glutamate Receptors by G Protein-Coupled Receptor Kinases: mGlu2 Receptors Are Resistant to Homologous Desensitization
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

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

L. Iacovelli, G. Molinaro, G. Battaglia, M. Motolese, L. Di Menna, M. Alfiero, J. Blahos, F. Matrisciano, M. Corsi, C. Corti, V. Bruno, A. De Blasi and F. Nicoletti
Molecular Pharmacology April 1, 2009, 75 (4) 991-1003; DOI: https://doi.org/10.1124/mol.108.052316

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleArticle

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

L. Iacovelli, G. Molinaro, G. Battaglia, M. Motolese, L. Di Menna, M. Alfiero, J. Blahos, F. Matrisciano, M. Corsi, C. Corti, V. Bruno, A. De Blasi and F. Nicoletti
Molecular Pharmacology April 1, 2009, 75 (4) 991-1003; DOI: https://doi.org/10.1124/mol.108.052316
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • GABAAR Molecular Identity in Oligodendrocytes
  • Editing TOP2α Intron-19 5′ SS Circumvents Drug Resistance
  • SerpinA3N and drug induced liver injury
Show more Articles

Similar Articles

  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics