Molecular impact of MinK on the enantiospecific block of I_Ks by chromanols

Slowly activating I_Ks (KCNQ1/MinK) channels were expressed in Xenopous oocytes and their sensitivity to chromanols was compared to homomeric KCNQ1 channels. To elucidate the contribution of the β-subunit Mink on chromanol block, a formerly described chromanol HMR 1556 and its enantiomer S5557 were tested for enantio-specificity in blocking I_Ks and KCNQ1 as shown for the single enantiomers of chromanol 293B. Both enantiomers blocked homomeric KCNQ1 channels to a lesser extent than heteromeric I_Ks channels. Furthermore, we expressed both WT and mutant Mink subunits to examine the involvement of particular Mink protein regions in channel block by chromanols, Through a broad variety of Mink deletion and point mutants, we could not identify amino acids or regions where sensitivity was abolished or strikingly diminished (>2.5 fold). This could indicate that Mink does not directly take part in chromanol binding but acts allosterically to facilitate drug binding to the principal subunit KCNQ1.