An outer pore blocker, TPeA+, or an inner cavity blocker, dofetilide (DOF) prevented the activator effect of PD307243 on hERG. A, cartoon of a TPeA+ ion binding to the outer pore entrance of hERG. B, time course of changes in hERG current amplitude before and after application of 50 μM TPeA+ and after application of increasing concentrations of PD in the continuous presence of TPeA+. Current amplitudes were measured from time-dependent currents during 1-s step to 0 mV and normalized by control. Inset: summary of PD (20 μM)-induced changes in hERG current amplitude in the absence or presence of TPeA+. C and D, the format is the same as that in A and B. DOF binds from the intracellular side of the membrane to the inner cavity.