Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain

► We investigate the molecular determinants of acacetin in blocking hKv1.5 channels. ► Acacetin blocks hKv1.5 channels in a use- and frequency-dependent manner. ► The natural flavone acacetin inhibits hKv1.5 channels by binding to the S6-domain.