Abstract
The class Ic antiarrhythmic drug flecainide inhibits KCNH2-encoded “hERG” potassium channels at clinically relevant concentrations. The aim of this study was to elucidate the underlying molecular basis of this action. Patch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37°C. Wild-type (WT) IhERG was inhibited with an IC50 of 1.49μM and this was not significantly altered by reversing the direction of K+ flux or raising external [K+]. The use of charged and uncharged flecainide analogues showed that the charged form of the drug accesses the channel from the cell interior to produce block. Promotion of WT IhERG inactivation slowed recovery from inhibition, whilst the N588K and S631A attenuated-inactivation mutants exhibited IC50 values 4–5 fold that of WT IhERG. The use of pore-helix/selectivity filter (T623A, S624A V625A) and S6 helix (G648A, Y652A, F656A) mutations showed <10-fold shifts in IC50 for all but V625A and F656A, which respectively exhibited IC50s 27-fold and 142-fold their WT controls. Docking simulations using a MthK-based homology model suggested an allosteric effect of V625A, since in low energy conformations flecainide lay too low in the pore to interact directly with that residue. On the other hand, the molecule could readily form π–π stacking interactions with aromatic residues and particularly with F656. We conclude that flecainide accesses the hERG channel from the cell interior on channel gating, binding low in the inner cavity, with the S6 F656 residue acting as a principal binding determinant.
Highlights
Flecainide is a class Ic antiarrhythmic drug that is used primarily in the treatment of supraventricular arrhythmias [1] in the absence of structural heart disease, it is sometimes used in the treatment of ventricular tachycardias that are resistant to other treatment
Concentration-dependent block of WT inhibitors of hERG current (IhERG) by flecainide was studied by the repeated application of the voltage protocol shown in the lower panel of Fig. 1A
Flecainide block of WT IhERG was studied under comparable experimental conditions
Summary
Flecainide is a class Ic antiarrhythmic drug that is used primarily in the treatment of supraventricular arrhythmias [1] in the absence of structural heart disease, it is sometimes used in the treatment of ventricular tachycardias that are resistant to other treatment. A 2011 review of 25 years of flecainide use supports the notion that, with appropriate patient selection, flecainide is safe and effective in AF management [5]. The importance of appropriate patient selection arises, to a significant extent, from the results of the CAST trial, which showed increased mortality with class Ic (flecainide and encainide) drug treatment of patients surviving myocardial infarction (MI) [6]. Recent evidence supports an additional clinical application of flecainide in the treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT), in cases where arrhythmias are not completely suppressed by β-blocker therapy Melgari et al / Journal of Molecular and Cellular Cardiology 86 (2015) 42–53 exhibited a reverse-rate/bradycardia dependence that is consistent with a role for IKr inhibition (e.g. [25,26,27,28])
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