Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels

Hai Huang, Silvia G. Priori, Carlo Napolitano, Michael E. O'Leary, Mohamed Chahine

Research output: Contribution to journalArticlepeer-review

Abstract

Long QT syndrome type 3 (LQT3) has been traced to mutations of the cardiac Na+ channel (Nav1.5) that produce persistent Na + currents leading to delayed ventricular repolarization and torsades de pointes. We performed mutational analyses of patients suffering from LQTS and characterized the biophysical properties of the mutations that we uncovered. One LQT3 patient carried a mutation in the SCN5A gene in which the cysteine was substituted for a highly conserved tyrosine (Y1767C) located near the cytoplasmic entrance of the Nav1.5 channel pore. The wild-type and mutant channels were transiently expressed in tsA201 cells, and Na+ currents were recorded using the patch-clamp technique. The Y1767C channel produced a persistent Na+ current, more rapid inactivation, faster recovery from inactivation, and an increased window current. The persistent Na+ current of the Y1767C channel was blocked by ranolazine but not by many class I antiarrhythmic drugs. The incomplete inactivation, along with the persistent activation of Na+ channels caused by an overlap of voltage-dependent activation and inactivation, known as window currents, appeared to contribute to the LQTS phenotype in this patient. The blocking effect of ranolazine on the persistent Na+ current suggested that ranolazine may be an effective therapeutic treatment for patients with this mutation. Our data also revealed the unique role for the Y1767 residue in inactivating and forming the intracellular pore of the Nav1.5 channel.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume300
Issue number1
DOIs
Publication statusPublished - Jan 2011

Keywords

  • Genetics
  • Long QT syndrome
  • Sodium channels
  • Ventricular arrhythmias
  • Voltage-gated sodium channels

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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