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

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

Benita Sjögren, Sergio Parra, Lauren J. Heath, Kevin B. Atkins, Zie-Jian Xie and Richard R. Neubig
Molecular Pharmacology September 2012, 82 (3) 500-509; DOI: https://doi.org/10.1124/mol.112.079293
Benita Sjögren
Departments of Pharmacology (B.S., S.P., L.J.H., R.R.N.) and Internal Medicine (K.B.A., R.R.N.), and Center for Chemical Genomics (R.R.N.), University of Michigan, Ann Arbor, Michigan; and Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, Ohio (Z.-J.X.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sergio Parra
Departments of Pharmacology (B.S., S.P., L.J.H., R.R.N.) and Internal Medicine (K.B.A., R.R.N.), and Center for Chemical Genomics (R.R.N.), University of Michigan, Ann Arbor, Michigan; and Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, Ohio (Z.-J.X.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lauren J. Heath
Departments of Pharmacology (B.S., S.P., L.J.H., R.R.N.) and Internal Medicine (K.B.A., R.R.N.), and Center for Chemical Genomics (R.R.N.), University of Michigan, Ann Arbor, Michigan; and Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, Ohio (Z.-J.X.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevin B. Atkins
Departments of Pharmacology (B.S., S.P., L.J.H., R.R.N.) and Internal Medicine (K.B.A., R.R.N.), and Center for Chemical Genomics (R.R.N.), University of Michigan, Ann Arbor, Michigan; and Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, Ohio (Z.-J.X.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zie-Jian Xie
Departments of Pharmacology (B.S., S.P., L.J.H., R.R.N.) and Internal Medicine (K.B.A., R.R.N.), and Center for Chemical Genomics (R.R.N.), University of Michigan, Ann Arbor, Michigan; and Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, Ohio (Z.-J.X.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard R. Neubig
Departments of Pharmacology (B.S., S.P., L.J.H., R.R.N.) and Internal Medicine (K.B.A., R.R.N.), and Center for Chemical Genomics (R.R.N.), University of Michigan, Ann Arbor, Michigan; and Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, Ohio (Z.-J.X.)
  • 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

Regulator of G protein signaling 2 (RGS2), a Gq-specific GTPase-activating protein, is strongly implicated in cardiovascular function. RGS2(−/−) mice are hypertensive and prone to heart failure, and several rare human mutations that accelerate RGS2 degradation have been identified among patients with hypertension. Therefore, pharmacological up-regulation of RGS2 protein levels might be beneficial. We used a β-galactosidase complementation method to screen several thousand compounds with known pharmacological functions for those that increased RGS2 protein levels. Several cardiotonic steroids (CTSs), including ouabain and digoxin, increased RGS2 but not RGS4 protein levels. CTSs increased RGS2 protein levels through a post-transcriptional mechanism, by slowing protein degradation. RGS2 mRNA levels in primary vascular smooth muscle cells were unaffected by CTS treatment, whereas protein levels were increased 2- to 3-fold. Na+/K+-ATPase was required for the increase in RGS2 protein levels, because the effect was lost in Na+/K+-ATPase-knockdown cells. Furthermore, we demonstrated that CTS-induced increases in RGS2 levels were functional and reduced receptor-stimulated, Gq-dependent, extracellular signal-regulated kinase phosphorylation. Finally, we showed that in vivo treatment with digoxin led to increased RGS2 protein levels in heart and kidney. CTS-induced increases in RGS2 protein levels and function might modify several deleterious mechanisms in hypertension and heart failure. This novel CTS mechanism might contribute to the beneficial actions of low-dose digoxin treatment in heart failure. Our results support the concept of small-molecule modulation of RGS2 protein levels as a new strategy for cardiovascular therapy.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA023252]; the Swedish Heart and Lung Foundation [Grant 20110193]; and Bristol-Meyers-Squibb (to R.R.N.).

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

    http://dx.doi.org/10.1124/mol.112.079293.

  • ABBREVIATIONS:

    CTS
    cardiotonic steroid
    GPCR
    G protein-coupled receptor
    RGS
    regulator of G protein signaling
    VSMC
    vascular smooth muscle cell
    PI
    phosphoinositide
    ERK
    extracellular signal-regulated kinase
    PAGE
    polyacrylamide gel electrophoresis
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    HEK
    human embryonic kidney
    TBS-T
    Tris-buffered saline-Tween 20
    shRNA
    short hairpin RNA
    HA
    hemagglutinin
    PCR
    polymerase chain reaction
    PL
    ProLabel
    MG-132
    N-(benzyloxycarbonyl)leucinylleucinylleucinal
    PP2
    4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine
    LY294002
    2-morpholin-4-yl-8-phenylchromen-4-one.

  • Received April 12, 2012.
  • Accepted June 13, 2012.
  • Copyright © 2012 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: 82 (3)
Molecular Pharmacology
Vol. 82, Issue 3
1 Sep 2012
  • 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.
Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels
(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

CTSs Stabilize RGS2 Protein Levels

Benita Sjögren, Sergio Parra, Lauren J. Heath, Kevin B. Atkins, Zie-Jian Xie and Richard R. Neubig
Molecular Pharmacology September 1, 2012, 82 (3) 500-509; DOI: https://doi.org/10.1124/mol.112.079293

Citation Manager Formats

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

Share
Research ArticleArticle

CTSs Stabilize RGS2 Protein Levels

Benita Sjögren, Sergio Parra, Lauren J. Heath, Kevin B. Atkins, Zie-Jian Xie and Richard R. Neubig
Molecular Pharmacology September 1, 2012, 82 (3) 500-509; DOI: https://doi.org/10.1124/mol.112.079293
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
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Cysteine151 in Keap1 Drives CDDO-Me Pharmacodynamic Action
  • Pharmacological Characterization of the Human α6β4 nAChR
  • Allosteric Modulation of Metabotropic Glutamate Receptor 1
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