Selective targeting of gain-of-function KCNQ1 mutations predisposing to atrial fibrillation

Courtney M. Campbell, Jonathan D. Campbell, Christopher H. Thompson, Eleonora Savio Galimberti, Dawood Darbar, Carlos G. Vanoye, Alfred L. George*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Background: Atrial fibrillation is the most common sustained cardiac arrhythmia in adults. We hypothesized that gain-offunction KCNQ1 mutations previously associated with familial atrial fibrillation have distinct pharmacological properties that may enable targeted inhibition. Methods and Results: Wild-type (WT) KCNQ1 or the familial atrial fibrillation mutation KCNQ1-S140G was heterologously coexpressed with KCNE1 to enable electrophysiological recording of the slow delayed rectifier current (I Ks) and investigation of pharmacological effects of the I Ks selective blocker HMR-1556. Coexpression of KCNQ1-S140G with KCNE1 generated potassium currents (S140G-IKs) that exhibited greater sensitivity to HMR-1556 than W T-IKs. Enhanced HMR-1556 sensitivity was also observed for another gain-of-function atrial fibrillation mutation, KCNQ1-V141M. Heteromeric expression of KCNE1 with both KCNQ1-WT and KCNQ1-S140G generated currents (HET-IKs) with gain-of-function features, including larger amplitude, a constitutively active component, hyperpolarized voltage dependence of activation, and extremely slow deactivation. A low concentration of HMR-1556, which had little effect on WT-IKs but was capable of inhibiting the mutant channel, reduced both instantaneous and steady state HET-IKs to levels that were not significantly different from WT-IKs and attenuated use-dependent accumulation of the current. In cultured adult rabbit left atrial myocytes, expression of S140G-IKs shortened action potential duration compared with W T-IKs. Application of HMR-1556 mitigated S140G-IKs-induced action potential duration shortening and did not alter action potential duration in cells expressing WT-IKs. Conclusions: The enhanced sensitivity of KCNQ1 gain-of-function mutations for HMR-1556 suggests the possibility of selective therapeutic targeting, and, therefore, our data illustrate a potential proof of principle for genotype-specific treatment of this heritable arrhythmia.

Original languageEnglish (US)
Pages (from-to)960-966
Number of pages7
JournalCirculation: Arrhythmia and Electrophysiology
Issue number5
StatePublished - Oct 2013


  • Antiarrhythmic drugs
  • Arrhythmias, cardiac
  • Atrial fibrillation
  • Genetics
  • Potassium channels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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