Pharmacological targeting of long QT mutant sodium channels

D. W. Wang, K. Yazawa, N. Makita, A. L. George, P. B. Bennett*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

141 Scopus citations


The congenital long QT syndrome (LQTS) is an inherited disorder characterized by a delay in cardiac cellular repolarization leading to cardiac arrhythmias and sudden death often in young people. One form of the disease (LQT3) involves mutations in the voltage-gated cardiac sodium channel. The potential for targeted suppression of the LQT defect was explored by heterologous expression of mutant channels in cultured human cells. Kinetic and steady state analysis revealed an enhanced apparent affinity for the predominantly charged, primary amine compound, mexiletine. The affinity of the mutant channels in the inactivated state was similar to the wild type (WT) channels (IC50 ~ 15-20 μM), but the late-opening channels were inhibited at significantly lower concentrations (IC50 = 2-3 μM) causing a preferential suppression of the late openings. The targeting of the defective behavior of the mutant channels has important implications for therapeutic intervention in this disease. The results provide insights for the selective suppression of the mutant phenotype by very low concentrations of drug and indicate that mexiletine equally suppresses the defect in all three known LQT3 mutants.

Original languageEnglish (US)
Pages (from-to)1714-1720
Number of pages7
JournalJournal of Clinical Investigation
Issue number7
StatePublished - Apr 1 1997


  • LQT3
  • Na channel
  • antiarrhythmic agent
  • hH1
  • human heart
  • mexiletine

ASJC Scopus subject areas

  • Medicine(all)


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