Cardiac Na+ channel dysfunction in Brugada syndrome is aggravated by β1-subunit

Naomasa Makita*, Nobumasa Shirai, Dao W. Wang, Koji Sasaki, Alfred L. George, Morio Kanno, Akira Kitabatake

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


Background - Mutations in the gene encoding the human cardiac Na+ channel α-subunit (hill) are responsible for chromosome 3-linked congenital long-QT syndrome (LQT3) and idiopathic ventricular fibrillation (IVF). An auxiliary β1-subunit, widely expressed in excitable tissues, shifts the voltage dependence of steady-state inactivation toward more negative potentials and restores normal gating kinetics of brain and skeletal muscle Na+ channels expressed in Xenopus oocytes but has little if any functional effect on the cardiac isoform. Here, we characterize the altered effects of a human β1-subunit (hβ1) on the heterologously expressed hill mutation (T1620M) previously associated with IVF. Methods and Results - When expressed alone in Xenopus oocytes, T1620M exhibited no persistent currents, in contrast to the LQT3 mutant channels, but the midpoint of steady-state inactivation (V(1/2)) was significantly shifted toward more positive potentials than for wild-type hH1. Coexpression of hβ1 did not significantly alter current decay or recovery from inactivation of wild-type hill; however, it further shifted the V(1/2) and accelerated the recovery from inactivation of T1620M. Oocyte macropatch analysis revealed that the activation kinetics of T1620M were normal. Conclusions - It is suggested that coexpression of hβ1 exposes a more severe functional defect that results ia a greater overlap in the relationship between channel inactivation and activation (window current) in T1620M, which is proposed to be a potential pathophysiological mechanism of IVF in vivo. One possible explanation for our finding is an altered α-/β1-subunit association in the mutant.

Original languageEnglish (US)
Pages (from-to)54-60
Number of pages7
Issue number1
StatePublished - Jan 4 2000


  • Action potentials
  • Arrhythmia
  • Death, sudden
  • Electrophysiology
  • Fibrillation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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