Abstract
Cardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD), either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs (KCNQ1+KCNE1), a slowly activating K+ current, plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage-sensing domain (VSD) of the IKs channel. Here, we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed the drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.
Keywords:
C28; IKs; KCNQ1; antiarrhythmia; voltage sensor domain.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Action Potentials / drug effects*
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Action Potentials / physiology
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Amino Acid Substitution
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Animals
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Arrhythmias, Cardiac / drug therapy
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Arrhythmias, Cardiac / genetics
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Arrhythmias, Cardiac / metabolism
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Arrhythmias, Cardiac / pathology
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Calcium / metabolism
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Dogs
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Furans / pharmacology
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Gene Expression
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Guinea Pigs
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Heart Atria / cytology
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Heart Atria / metabolism
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Heart Ventricles / cytology
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Heart Ventricles / metabolism
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Humans
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KCNQ1 Potassium Channel / chemistry
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KCNQ1 Potassium Channel / genetics*
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KCNQ1 Potassium Channel / metabolism
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Moxifloxacin / pharmacology
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism*
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Oocytes / cytology
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Oocytes / drug effects
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Oocytes / metabolism
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Patch-Clamp Techniques
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Phenethylamines / pharmacology
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Potassium / metabolism
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Primary Cell Culture
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Pyridines / pharmacology
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Pyrimidines / pharmacology
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Small Molecule Libraries / pharmacology*
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Sodium / metabolism
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Sulfonamides / pharmacology
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Transgenes
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Xenopus laevis
Substances
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Furans
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KCNQ1 Potassium Channel
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KCNQ1 protein, human
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PI103
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Phenethylamines
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Pyridines
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Pyrimidines
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Small Molecule Libraries
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Sulfonamides
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Sodium
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dofetilide
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Potassium
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Calcium
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Moxifloxacin