Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor

Christie M. McBride, Ashley M. Smith, Jennifer L. Smith, Allison R. Reloj, Ellyn J. Velasco, Jonathan Powell, Claude S. Elayi, Daniel C. Bartos, Don E. Burgess, Brian P. Delisle

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (I Kr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing I Kr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (I Kv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients' genotypes) mostly corrected the changes in I Kv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing I Kr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease I Kr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient.

Original languageEnglish
Pages (from-to)355-364
Number of pages10
JournalJournal of Membrane Biology
Volume246
Issue number5
DOIs
StatePublished - May 2013

Bibliographical note

Funding Information:
This work was supported by the American Heart Association predoctoral award PRE7370003 (to D. C. B.) and the National Heart Lung and Blood Institute grant R01 HL087039 (to B. P. D.).

Keywords

  • Arrhythmia
  • Channel gating
  • Long QT syndrome
  • Potassium ion channel
  • Trafficking

ASJC Scopus subject areas

  • Biophysics
  • Physiology
  • Cell Biology

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