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 ArticleNeuropharmacology

Inhibition of Plasma Membrane Na/Ca-Exchanger by KB-R7943 or Lithium Reveals Its Role in Ca-Dependent N-methyl-d-aspartate Receptor Inactivation

Dmitry A. Sibarov, Polina A. Abushik, Ekaterina E. Poguzhelskaya, Konstantin V. Bolshakov and Sergei M. Antonov
Journal of Pharmacology and Experimental Therapeutics December 2015, 355 (3) 484-495; DOI: https://doi.org/10.1124/jpet.115.227173
Dmitry A. Sibarov
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, St. Petersburg, Russia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Dmitry A. Sibarov
Polina A. Abushik
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, St. Petersburg, Russia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ekaterina E. Poguzhelskaya
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, St. Petersburg, Russia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Konstantin V. Bolshakov
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, St. Petersburg, Russia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sergei M. Antonov
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, St. Petersburg, Russia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Sergei M. Antonov
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Visual Overview

Figure
  • Download figure
  • Open in new tab
  • Download powerpoint

Abstract

To evaluate the possible role of the plasma membrane Na+/Ca2+-exchanger (NCX) in regulation of N-methyl-d-aspartate (NMDA) receptors (NMDARs), we studied effects of 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea methanesulfonate (KB-R7943; KBR) and lithium (inhibitors of NCX) on NMDA-elicited whole-cell currents using the patch-clamp technique on rat cortical neurons and human embryonic kidney 293T cells expressing recombinant NMDARs. KBR inhibited NMDAR currents in a voltage-independent manner with similar potency for receptors of GluN1/2A and GluN1/2B subunit compositions that excludes open-channel block and GluN2B-selective inhibition. The inhibition by KBR depended on glycine (Gly) concentration. At 30 μM NMDA, the KBR IC50 values were 5.3 ± 0.1 and 41.2 ± 8.8 μM for 1 and 300 μM Gly, respectively. Simultaneous application of NMDA + KBR in the absence of Gly induced robust inward NMDAR currents that peaked and then rapidly decreased. KBR, therefore, is an agonist (EC50 is 1.18 ± 0.16 µM) of the GluN1 subunit coagonist binding sites. The decrease of NMDA-elicited currents in the presence of KBR was abolished in Ca2+-free solution and was not observed in the presence of extracellular Ca2+ on 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid-loaded neurons, suggesting that Ca2+ affects NMDARs from the cytosol. In agreement, the substitution of Li+ for extracellular Na+ caused a considerable decrease of NMDAR currents, which was not observed in the absence of extracellular Ca2+. Most likely, the accumulation of intracellular Ca2+ is caused by the inhibition of Ca2+ extrusion via NCX. Thus, KBR and Li+ provoke Ca2+-dependent receptor inactivation due to the disruption of Ca2+ extrusion by the NCX. The data reveal the role of NCX in regulation of Ca2+-dependent inactivation of NMDARs.

Footnotes

    • Received June 23, 2015.
    • Accepted September 18, 2015.
  • This work was supported by the Russian Foundation for Basic Research [Grants 14-04-00227 (to S.M.A.), 15-04-08283 (to D.A.S.), and 14-04-31707 (to P.A.A.)] and by the program grant (Section of Physiology and Fundamental Medicine) of Russian Academy of Sciences (to S.M.A.).

  • dx.doi.org/10.1124/jpet.115.227173.

  • Copyright © 2015 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: 355 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 355, Issue 3
1 Dec 2015
  • 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.
Inhibition of Plasma Membrane Na/Ca-Exchanger by KB-R7943 or Lithium Reveals Its Role in Ca-Dependent N-methyl-d-aspartate Receptor Inactivation
(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 ArticleNeuropharmacology

Mechanism of KB-R7943 and Lithium Effects on NMDARs

Dmitry A. Sibarov, Polina A. Abushik, Ekaterina E. Poguzhelskaya, Konstantin V. Bolshakov and Sergei M. Antonov
Journal of Pharmacology and Experimental Therapeutics December 1, 2015, 355 (3) 484-495; DOI: https://doi.org/10.1124/jpet.115.227173

Citation Manager Formats

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

Share
Research ArticleNeuropharmacology

Mechanism of KB-R7943 and Lithium Effects on NMDARs

Dmitry A. Sibarov, Polina A. Abushik, Ekaterina E. Poguzhelskaya, Konstantin V. Bolshakov and Sergei M. Antonov
Journal of Pharmacology and Experimental Therapeutics December 1, 2015, 355 (3) 484-495; DOI: https://doi.org/10.1124/jpet.115.227173
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
    • Visual Overview
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Glycine receptor modulation using monoclonal antibodies
  • Iclepertin (BI 425809) in Schizophrenia-Related Models
  • D1 Agonist Versus Methylphenidate on PFC Working Memory
Show more Neuropharmacology

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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics