Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • 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
  • Submit
  • 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
Journal of Pharmacology and Experimental Therapeutics
  • 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
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • 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
  • Submit
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleCellular and Molecular

Salt Bridges Overlapping the Gonadotropin-Releasing Hormone Receptor Agonist Binding Site Reveal a Coincidence Detector for G Protein-Coupled Receptor Activation

Jo Ann Janovick, Irina D. Pogozheva, Henry I. Mosberg and P. Michael Conn
Journal of Pharmacology and Experimental Therapeutics August 2011, 338 (2) 430-442; DOI: https://doi.org/10.1124/jpet.111.180869
Jo Ann Janovick
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Irina D. Pogozheva
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Henry I. Mosberg
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
P. Michael Conn
  • 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

G protein-coupled receptors (GPCRs) play central roles in most physiological functions, and mutations in them cause heritable diseases. Whereas crystal structures provide details about the structure of GPCRs, there is little information that identifies structural features that permit receptors to pass the cellular quality control system or are involved in transition from the ground state to the ligand-activated state. The gonadotropin-releasing hormone receptor (GnRHR), because of its small size among GPCRs, is amenable to molecular biological approaches and to computer modeling. These techniques and interspecies comparisons are used to identify structural features that are important for both intracellular trafficking and GnRHR activation yet distinguish between these processes. Our model features two salt (Arg38-Asp98 and Glu90-Lys121) and two disulfide (Cys14-Cys200 and Cys114-Cys196) bridges, all of which are required for the human GnRHR to traffic to the plasma membrane. This study reveals that both constitutive and ligand-induced activation are associated with a “coincidence detector” that occurs when an agonist binds. The observed constitutive activation of receptors lacking Glu90-Lys121, but not Arg38-Asp98 ionic bridge, suggests that the role of the former connection is holding the receptor in the inactive conformation. Both the aromatic ring and hydroxyl group of Tyr284 and the hydrogen bonding of Ser217 are important for efficient receptor activation. Our modeling results, supported by the observed influence of Lys191 from extracellular loop 2 (EL2) and a four-residue motif surrounding this loop on ligand binding and receptor activation, suggest that the positioning of EL2 within the seven-α-helical bundle regulates receptor stability, proper trafficking, and function.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK85040] (to P.M.C.); the National Institutes of Health National Center for Research Resources [Grants RR030229, RR000163] (to P.M.C.); the National Institutes of Health National Institute on Drug Abuse [Grant DA003910] (to H.I.M.); and by the National Science Foundation [Grant 0849713] (Division of Biological Infrastructure) (to I.D.P.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.180869.

  • ABBREVIATIONS:

    GnRH
    gonadotropin-releasing hormone
    GnRHR
    gonadotropin-releasing hormone receptor
    hGnRHR
    human GnRHR
    QCS
    quality control system
    ER
    endoplasmic reticulum
    GPCR
    G protein-coupled receptors
    PM
    plasma membrane
    TM
    transmembrane segment
    CA
    constitutive activity
    WT
    wild type
    EL
    extracellular loop
    DMEM
    Dulbecco's modified Eagle's medium
    BSA
    bovine serum albumin
    IP
    inositol phosphate.

  • Received March 1, 2011.
  • Accepted April 27, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET 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

Journal of Pharmacology and Experimental Therapeutics: 338 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 2
1 Aug 2011
  • 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 Journal of Pharmacology and Experimental Therapeutics 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.
Salt Bridges Overlapping the Gonadotropin-Releasing Hormone Receptor Agonist Binding Site Reveal a Coincidence Detector for G Protein-Coupled Receptor Activation
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleCellular and Molecular

Salt Bridges Overlapping the Gonadotropin-Releasing Hormone Receptor Agonist Binding Site Reveal a Coincidence Detector for G Protein-Coupled Receptor Activation

Jo Ann Janovick, Irina D. Pogozheva, Henry I. Mosberg and P. Michael Conn
Journal of Pharmacology and Experimental Therapeutics August 1, 2011, 338 (2) 430-442; DOI: https://doi.org/10.1124/jpet.111.180869

Citation Manager Formats

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

Share
Research ArticleCellular and Molecular

Salt Bridges Overlapping the Gonadotropin-Releasing Hormone Receptor Agonist Binding Site Reveal a Coincidence Detector for G Protein-Coupled Receptor Activation

Jo Ann Janovick, Irina D. Pogozheva, Henry I. Mosberg and P. Michael Conn
Journal of Pharmacology and Experimental Therapeutics August 1, 2011, 338 (2) 430-442; DOI: https://doi.org/10.1124/jpet.111.180869
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

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

Related Articles

Cited By...

More in this TOC Section

  • Chlorogenic Acid Inhibits Breast Cancer Metastasis
  • SNAP25 and mGluRs Control Pathological Tau Release
  • N-Stearoylethanolamine Inhibits Platelet Reactivity
Show more Cellular and Molecular

Similar Articles

Advertisement
  • 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 JPET
  • 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
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics