action potential clamp and mefloquine sensitivity of recombinant i ks channels incorporating the v307l kcnq1 mutation the slow delayed rectifier potassium current iks contributes to repolarisation of cardiac ventricular action potentials and thereby to the duration of the qt interval of the electrocardiogram mutations to iks channel subunits occur in clinically significant cardiac repolarisation disorders the short qt syndrome sqts is associated with accelerated ventricular repolarisation and with an increased risk of arrhythmia and sudden death the sqt2 variant of the sqts has been linked to a gainoffunction aminoacid substitution v307l in the kcnq1encoded iks channel alphasubunit this study reports the first action potential ap voltageclamp comparison between wildtype wt and v307l kcnq1 coexpressed with kcne1 to recapitulate iks and identifies an effective pharmacological inhibitor of recombinant iks channels incorporating the v307l kcnq1 mutation perforatedpatch voltageclamp recordings at 37 degrees c of wholecell current carried by coexpressed kcnq1 and kcne1 showed a marked 36 mv shift in halfmaximal activation for v307l compared to wt kcnq1 a significant slowing of current deactivation was also observed under ap clamp peak repolarising current was significantly augmented for v307l kcnq1 compared to wt kcnq1 for both ventricular and atrial ap commands consistent with an ability of the v307l mutation to increase repolarising iks in both regions the quinoline agent mefloquine inhibited wt kcnq1kcne1 with an ic50 of 34 mum compared to 33 mum for v307l kcnq1kcne1 p 005 this establishes mefloquine as an effective inhibitor of recombinant iks channels incorporating this sqt2 kcnq1 mutation