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

D1-D2 Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

Lani S. Chun, R. Benjamin Free, Trevor B. Doyle, Xi-Ping Huang, Michele L. Rankin and David R. Sibley
Molecular Pharmacology August 2013, 84 (2) 190-200; DOI: https://doi.org/10.1124/mol.113.085175
Lani S. Chun
Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (L.S.C., R.B.F., T.B.D., M.L.R., D.R.S.); Cellular, Molecular, Developmental Biology & Biophysics Program, Johns Hopkins University, Baltimore, Maryland (L.S.C.); and National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (X.-P.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
R. Benjamin Free
Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (L.S.C., R.B.F., T.B.D., M.L.R., D.R.S.); Cellular, Molecular, Developmental Biology & Biophysics Program, Johns Hopkins University, Baltimore, Maryland (L.S.C.); and National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (X.-P.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Trevor B. Doyle
Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (L.S.C., R.B.F., T.B.D., M.L.R., D.R.S.); Cellular, Molecular, Developmental Biology & Biophysics Program, Johns Hopkins University, Baltimore, Maryland (L.S.C.); and National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (X.-P.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xi-Ping Huang
Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (L.S.C., R.B.F., T.B.D., M.L.R., D.R.S.); Cellular, Molecular, Developmental Biology & Biophysics Program, Johns Hopkins University, Baltimore, Maryland (L.S.C.); and National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (X.-P.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michele L. Rankin
Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (L.S.C., R.B.F., T.B.D., M.L.R., D.R.S.); Cellular, Molecular, Developmental Biology & Biophysics Program, Johns Hopkins University, Baltimore, Maryland (L.S.C.); and National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (X.-P.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David R. Sibley
Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (L.S.C., R.B.F., T.B.D., M.L.R., D.R.S.); Cellular, Molecular, Developmental Biology & Biophysics Program, Johns Hopkins University, Baltimore, Maryland (L.S.C.); and National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (X.-P.H.)
  • 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 + SI
  • PDF
Loading

Abstract

The D1 dopamine receptor (D1R) has been proposed to form a hetero-oligomer with the D2 dopamine receptor (D2R), which in turn results in a complex that couples to phospholipase C–mediated intracellular calcium release. We have sought to elucidate the pharmacology and mechanism of action of this putative signaling pathway. Dopamine dose-response curves assaying intracellular calcium mobilization in cells heterologously expressing the D1 and D2 subtypes, either alone or in combination, and using subtype selective ligands revealed that concurrent stimulation is required for coupling. Surprisingly, characterization of a putative D1-D2 heteromer-selective ligand, 6-chloro-2,3,4,5-tetrahydro-3-methyl-1-(3-methylphenyl)-1H-3-benzazepine-7,8-diol (SKF83959), found no stimulation of calcium release, but it did find a broad range of cross-reactivity with other G protein–coupled receptors. In contrast, SKF83959 appeared to be an antagonist of calcium mobilization. Overexpression of Gqα with the D1 and D2 dopamine receptors enhanced the dopamine-stimulated calcium response. However, this was also observed in cells expressing Gqα with only the D1R. Inactivation of Gi or Gs with pertussis or cholera toxin, respectively, largely, but not entirely, reduced the calcium response in D1R and D2R cotransfected cells. Moreover, sequestration of Gβγ subunits through overexpression of G protein receptor kinase 2 mutants either completely or largely eliminated dopamine-stimulated calcium mobilization. Our data suggest that the mechanism of D1R/D2R–mediated calcium signaling involves more than receptor-mediated Gq protein activation, may largely involve downstream signaling pathways, and may not be completely heteromer-specific. In addition, SKF83959 may not exhibit selective activation of D1-D2 heteromers, and its significant cross-reactivity to other receptors warrants careful interpretation of its use in vivo.

Footnotes

    • Received January 24, 2013.
    • Accepted May 16, 2013.
  • This work was supported in part by the Intramural Research Program of the National Institutes of Health [National Institute of Neurological Disorders and Stroke]; and the National Institutes of Health National Institute of Mental Health Psychoactive Drug Screening Program.

  • dx.doi.org/10.1124/mol.113.085175.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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: 84 (2)
Molecular Pharmacology
Vol. 84, Issue 2
1 Aug 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 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.
D1-D2 Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms
(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

D1-D2 Receptor Synergy and Ca2+ Signaling

Lani S. Chun, R. Benjamin Free, Trevor B. Doyle, Xi-Ping Huang, Michele L. Rankin and David R. Sibley
Molecular Pharmacology August 1, 2013, 84 (2) 190-200; DOI: https://doi.org/10.1124/mol.113.085175

Citation Manager Formats

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

Share
Research ArticleArticle

D1-D2 Receptor Synergy and Ca2+ Signaling

Lani S. Chun, R. Benjamin Free, Trevor B. Doyle, Xi-Ping Huang, Michele L. Rankin and David R. Sibley
Molecular Pharmacology August 1, 2013, 84 (2) 190-200; DOI: https://doi.org/10.1124/mol.113.085175
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
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • The binding site for KCI807 in the androgen receptor
  • Fatty acid amide hydrolase in cisplatin nephrotoxicity
  • eCB Signaling System in hiPSC-Derived Neuronal Cultures
Show more Articles

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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics