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
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
    • 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 molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Catechol-Binding Serines of β2-Adrenergic Receptors Control the Equilibrium between Active and Inactive Receptor States

Caterina Ambrosio, Paola Molinari, Susanna Cotecchia and Tommaso Costa
Molecular Pharmacology January 2000, 57 (1) 198-210;
Caterina Ambrosio
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paola Molinari
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susanna Cotecchia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tommaso Costa
  • 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

The binding free energy for the interaction between serines 204 and 207 of the fifth transmembrane helix of the β2-adrenergic receptor (β2-AR) and catecholic hydroxyl (OH) groups of adrenergic agonists was analyzed using double mutant cycles. Binding affinities for catecholic and noncatecholic agonists were measured in wild-type and mutant receptors, carrying alanine replacement of the two serines (S204A, S207A β2-AR), a constitutive activating mutation, or both. The free energy coupling between the losses of binding energy attributable to OH deletion from the ligand and from the receptor indicates a strong interaction (nonadditivity) as expected for a direct binding between the two sets of groups. However, we also measured a significant interaction between the deletion of OH groups from the receptor and the constitutive activating mutation. This suggests that a fraction of the decrease in agonist affinity caused by serine mutagenesis may involve a shift in the conformational equilibrium of the receptor toward the inactive state. Direct measurements using a transient transfection assay confirm this prediction. The constitutive activity of the (S204A, S207A) β2-AR mutant is 50 to 60% lower than that of the wild-type β2-AR. We conclude that S204 and S207 do not only provide a docking site for the agonist, but also control the equilibrium of the receptor between active (R*) and inactive (R) forms.

Footnotes

  • Send reprint requests to: Dr. Tommaso Costa, Laboratorio di Farmacologia, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail:tomcosta{at}iss.it

  • We acknowledge support from the EU BIOMED 2 program “Inverse Agonism. Implications for Drug Design” (to T.C.) and from the Fonds National Suisse de la Recherche Scientifique, Grant 31-51043.97 (to S.C.).

  • Abbreviations:
    7TM
    7 transmembrane domains
    β2-AR
    β2-adrenergic receptor
    AA
    S204A, S207A mutation
    CHO
    Chinese hamster ovary
    cam
    constitutive active mutant
    mape
    (±)2-(methylamino)-1-phenyl-1-ethanol
    • Received May 24, 1999.
    • Accepted October 1, 1999.
  • 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: 57 (1)
Molecular Pharmacology
Vol. 57, Issue 1
1 Jan 2000
  • Table of Contents
  • About the Cover
  • Index by author
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.
Catechol-Binding Serines of β2-Adrenergic Receptors Control the Equilibrium between Active and Inactive Receptor States
(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

Catechol-Binding Serines of β2-Adrenergic Receptors Control the Equilibrium between Active and Inactive Receptor States

Caterina Ambrosio, Paola Molinari, Susanna Cotecchia and Tommaso Costa
Molecular Pharmacology January 1, 2000, 57 (1) 198-210;

Citation Manager Formats

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

Share
Research ArticleArticle

Catechol-Binding Serines of β2-Adrenergic Receptors Control the Equilibrium between Active and Inactive Receptor States

Caterina Ambrosio, Paola Molinari, Susanna Cotecchia and Tommaso Costa
Molecular Pharmacology January 1, 2000, 57 (1) 198-210;
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
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Effects of Small Molecule Ligands on ACKR3 Receptors
  • Michaelis-Menten Quantification of GPCR-G Protein Signaling
  • Anti-aromatase activity of exemestane phase II metabolites
Show more Article

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 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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics