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 ArticleDrug Discovery and Translational Medicine

Kinetics of 5-HT2B Receptor Signaling: Profound Agonist-Dependent Effects on Signaling Onset and Duration

David J. Unett, Joel Gatlin, Todd L. Anthony, Daniel J. Buzard, Steve Chang, Chuan Chen, Xiaohua Chen, Huong T.-M. Dang, John Frazer, Minh K. Le, Abu J. M. Sadeque, Charles Xing and Ibragim Gaidarov
Journal of Pharmacology and Experimental Therapeutics December 2013, 347 (3) 645-659; DOI: https://doi.org/10.1124/jpet.113.207670
David J. Unett
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joel Gatlin
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Todd L. Anthony
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel J. Buzard
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steve Chang
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chuan Chen
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiaohua Chen
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Huong T.-M. Dang
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John Frazer
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Minh K. Le
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Abu J. M. Sadeque
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Charles Xing
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ibragim Gaidarov
Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California
  • 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 kinetics of drug-receptor interactions can profoundly influence in vivo and in vitro pharmacology. In vitro, the potencies of slowly associating agonists may be underestimated in assays capturing transient signaling events. When divergent receptor-mediated signaling pathways are evaluated using combinations of equilibrium and transient assays, potency differences driven by kinetics may be erroneously interpreted as biased signaling. In vivo, drugs with slow dissociation rates may display prolonged physiologic effects inconsistent with their pharmacokinetic profiles. We evaluated a panel of 5-hydroxytryptamine2B (5-HT2B) receptor agonists in kinetic radioligand binding assays and in transient, calcium flux assays, and inositol phosphate accumulation assays; two functional readouts emanating from Gαq-mediated activation of phospholipase C. In binding studies, ergot derivatives demonstrated slow receptor association and dissociation rates, resulting in significantly reduced potency in calcium assays relative to inositol phosphate accumulation assays. Ergot potencies for activation of extracellular signal-regulated kinases 1 and 2 were also highly time-dependent. A number of ergots produced wash-resistant 5-HT2B signaling that persisted for many hours without appreciable loss of potency, which was not explained simply by slow receptor-dissociation kinetics. Mechanistic studies indicated that persistent signaling originated from internalized or sequestered receptors. This study provides a mechanistic basis for the long durations of action in vivo and wash-resistant effects in ex vivo tissue models often observed for ergots. The 5-HT2B agonist activity of a number of ergot-derived therapeutics has been implicated in development of cardiac valvulopathy in man. The novel, sustained nature of ergot signaling reported here may represent an additional mechanism contributing to the valvulopathic potential of these compounds.

Footnotes

    • Received July 1, 2012.
    • Accepted September 17, 2013.
  • dx.doi.org/10.1124/jpet.113.207670.

  • Copyright © 2013 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: 347 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 347, Issue 3
1 Dec 2013
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • 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.
Kinetics of 5-HT2B Receptor Signaling: Profound Agonist-Dependent Effects on Signaling Onset and Duration
(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 ArticleDrug Discovery and Translational Medicine

5-HT2B Agonist Kinetics and Their Functional Consequences

David J. Unett, Joel Gatlin, Todd L. Anthony, Daniel J. Buzard, Steve Chang, Chuan Chen, Xiaohua Chen, Huong T.-M. Dang, John Frazer, Minh K. Le, Abu J. M. Sadeque, Charles Xing and Ibragim Gaidarov
Journal of Pharmacology and Experimental Therapeutics December 1, 2013, 347 (3) 645-659; DOI: https://doi.org/10.1124/jpet.113.207670

Citation Manager Formats

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

Share
Research ArticleDrug Discovery and Translational Medicine

5-HT2B Agonist Kinetics and Their Functional Consequences

David J. Unett, Joel Gatlin, Todd L. Anthony, Daniel J. Buzard, Steve Chang, Chuan Chen, Xiaohua Chen, Huong T.-M. Dang, John Frazer, Minh K. Le, Abu J. M. Sadeque, Charles Xing and Ibragim Gaidarov
Journal of Pharmacology and Experimental Therapeutics December 1, 2013, 347 (3) 645-659; DOI: https://doi.org/10.1124/jpet.113.207670
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

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

Related Articles

Cited By...

More in this TOC Section

  • Midazolam compared with tezampanel-caramiphen against soman
  • ERR agonist reduces obesity
  • Mechanistic Modeling of Humoral Immunity in NHPs
Show more Drug Discovery and Translational Medicine

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