Dual effects of mefenamic acid on the IKs molecular complex

Abstract Background and Purpose Mutations in both KCNQ1 and KCNE1, which together form the cardiac I Ks current, are associated with inherited conditions such as long and short QT syndromes. Mefenamic acid, a non‐steroidal anti‐inflammatory drug, is an I Ks potentiator and may be utilised as an archetype to design therapeutically useful I Ks agonists. However, here we show that mefenamic acid can also act as an I Ks inhibitor, and our data reveal its dual effects on KCNQ1/KCNE1 channels. Experimental Approach Effects of mefenamic acid on wild type (WT) and mutant KCNQ1/KCNE1 channels expressed in tsA201 cells were studied using whole cell patch clamp. Molecular dynamics simulations were used to determine trajectory clustering. Key Results Mefenamic acid inhibits WT I Ks at high concentrations while preserving some attributes of current potentiation. Inhibitory actions of mefenamic acid are unmasked at lower drug concentrations by KCNE1 and KCNQ1 mutations in the mefenamic acid binding pocket, at the extracellular end of KCNE1 and in the KCNQ1 S6 helix. Mefenamic acid does not inhibit KCNQ1 in the absence of KCNE1 but inhibits I Ks current in a concentration‐dependent manner in the mutant channels. Inhibition involves modulation of pore kinetics and/or voltage sensor domain‐pore coupling in WT and in the KCNE1 E43C mutant. Conclusion and Implications This work highlights the importance of structural motifs at the extracellular inter‐subunit interface of KCNQ1 and KCNE1 channels, and their interactions, in determining the nature of drug effects on the I Ks channel complex and has important implications for treating patients with specific long QT mutations.