Molecular basis of hERG potassium channel blockade by the class Ic antiarrhythmic flecainide.

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 W

SUBMITTER: Melgari D 

PROVIDER: S-EPMC4564290 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature