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Aim: The objectives of this study were to investigate the inhibitory action of verapamil on wild-type(WT) and mutation HERG K + channel current (I HERG ), and to determine whether mutations in the S6 region are important for the inhibition of I HERG by verapamil. Methods: HERG channels (WT, Y652A, and F656A) were expressed in oocytes of Xenopus laevis and studied using the 2-electrode voltage-clamp technique. Results: WT HERG is blocked in a concentration-dependent manner by verapamil (half-maximal inhibition concentration [IC 50 ]=5.1 µmol/L), and the steady state activation and inactivation parameters are shifted to more negative values. However, mutation to Ala of Y652 and F656 located on the S6 domain produced 16-fold and 20-fold increases in IC 50 for I HERG blockade, respectively. Simultaneously, the steady state activation and inactivation parameters for Y652A are also shifted to more negative values in the presence of the blockers. Conclusion: Verapamil preferentially binds to and blocks open HERG channels. Tyr-652 and Phe-656, 2 aromatic amino-acid residues in the inner (S6) helix, are critical in the verapamil-binding site.