title: Selective targeting of gain-of-function KCNQ1 mutations predisposing to atrial fibrillation.
abstract: BACKGROUND
  Atrial fibrillation is the most common sustained cardiac arrhythmia in adults. We hypothesized that gain-of-function KCNQ1 mutations previously associated with familial atrial fibrillation have distinct pharmacological properties that may enable targeted inhibition.
  
  
  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 (IKs) and investigation of pharmacological effects of the IKs selective blocker HMR-1556. Coexpression of KCNQ1-S140G with KCNE1 generated potassium currents (S140G-IKs) that exhibited greater sensitivity to HMR-1556 than WT-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 WT-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.
authors.affiliation: Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, TN; and Department of Engineering Management, Information, and Systems, Southern Methodist University, Dallas, TX.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Campbell
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Campbell
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Thompson
authors.forename: Eleonora Savio
authors.initials: ES
authors.lastname: Galimberti
authors.forename: Dawood
authors.initials: D
authors.lastname: Darbar
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Vanoye
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D003412:Cricetulus; D020022:Genetic Predisposition to Disease; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D009154:Mutation; D032383:Myocytes, Cardiac; D018408:Patch-Clamp Techniques; D010957:Plasmids; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D011817:Rabbits; D012307:Risk Factors; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D002839:Chromans; C420023:HMR 1556; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides
keywords: antiarrhythmic drugs; arrhythmias, cardiac; atrial fibrillation; genetics; potassium channels