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

Unexpected Mexiletine Responses of a Mutant Cardiac Na+ Channel Implicate the Selectivity Filter as a Structural Determinant of Antiarrhythmic Drug Access

Koji Sasaki, Naomasa Makita, Akihiko Sunami, Harumizu Sakurada, Nobumasa Shirai, Hisataka Yokoi, Akinori Kimura, Noritsugu Tohse, Masayasu Hiraoka and Akira Kitabatake
Molecular Pharmacology August 2004, 66 (2) 330-336; DOI: https://doi.org/10.1124/mol.66.2.330
Koji Sasaki
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Naomasa Makita
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Akihiko Sunami
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Harumizu Sakurada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nobumasa Shirai
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hisataka Yokoi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Akinori Kimura
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Noritsugu Tohse
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Masayasu Hiraoka
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Akira Kitabatake
  • 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

Gating properties of Na+ channels are the critical determinants for the state-dependent block by class I antiarrhythmic drugs; however, recent site-directed mutagenesis studies have shown that the Na+ channel selectivity filter region controls drug access to and dissociation from the binding site. To validate these observations, we have exploited a naturally occurring cardiac Na+ channel mutation, S1710L, located next to the putative selectivity filter residue of domain 4, and evaluated the pharmacological properties to mexiletine using whole-cell, patch-clamp recordings. Consistent with the large negative shift of steady-state inactivation and the enhanced slow inactivation, the S1710L channel showed greater mexiletine tonic block than wild-type (WT) channel. In contradiction, S1710L showed attenuated use-dependent block by mexiletine and accelerated recovery from block, suggesting that the drug escape though the external access path is facilitated. Extracellularly applied QX-314, a membrane-impermeant derivative of lidocaine, elicited significantly enhanced tonic block in S1710L similar to mexiletine. However, recovery from internally applied QX-314 was accelerated by 4.4-fold in S1710L compared with WT. These results suggest that the drug access to and dissociation from the binding site through the hydrophilic path are substantially altered. Moreover, K+ permeability was 1.9-fold increased in S1710L, verifying that the mutated residue is located in the ion-conducting pore. We propose that the Na+ channel selectivity filter region is a structural determinant for the antiarrhythmic drug sensitivity in addition to gating properties of the indigenous Na+ channels that govern the state-dependent drug block.

  • Received February 2, 2004.
  • Accepted May 20, 2004.
  • 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: 66 (2)
Molecular Pharmacology
Vol. 66, Issue 2
1 Aug 2004
  • 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.
Unexpected Mexiletine Responses of a Mutant Cardiac Na+ Channel Implicate the Selectivity Filter as a Structural Determinant of Antiarrhythmic Drug Access
(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

Unexpected Mexiletine Responses of a Mutant Cardiac Na+ Channel Implicate the Selectivity Filter as a Structural Determinant of Antiarrhythmic Drug Access

Koji Sasaki, Naomasa Makita, Akihiko Sunami, Harumizu Sakurada, Nobumasa Shirai, Hisataka Yokoi, Akinori Kimura, Noritsugu Tohse, Masayasu Hiraoka and Akira Kitabatake
Molecular Pharmacology August 1, 2004, 66 (2) 330-336; DOI: https://doi.org/10.1124/mol.66.2.330

Citation Manager Formats

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

Share
Research ArticleArticle

Unexpected Mexiletine Responses of a Mutant Cardiac Na+ Channel Implicate the Selectivity Filter as a Structural Determinant of Antiarrhythmic Drug Access

Koji Sasaki, Naomasa Makita, Akihiko Sunami, Harumizu Sakurada, Nobumasa Shirai, Hisataka Yokoi, Akinori Kimura, Noritsugu Tohse, Masayasu Hiraoka and Akira Kitabatake
Molecular Pharmacology August 1, 2004, 66 (2) 330-336; DOI: https://doi.org/10.1124/mol.66.2.330
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
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • 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 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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics