Figure 3.

High affinity block by terfenadine and cisapride is preserved in I663P trapped open channels. (A–D) Typical WT and I663P currents recorded with 30 mM external K⁺ evoked during repetitive application of the voltage protocol shown in the insets and in the presence of the indicated concentration of terfenadine (A and B) or cisapride (C and D). The pulse frequency was 0.14 Hz, such that channels were held at the holding potential for 1 s between successive sweeps. In both WT and I663P channels, peak tail current was inhibited in a concentration dependent manner. Traces shown represent steady-state conditions at each concentration. (E and F) Concentration-effect relationship for block of WT and I663P channels by terfenadine (E) and cisapride (F), plotted from peak tail current amplitudes recorded in experiments such as in (A–D). Peak tail current amplitudes in the presence of drug were normalized to peak tail currents in the absence of drug. Fits of WT data to the Hill equation (see Material and Methods) yielded values for IC₅₀ and n of: 4.4 ± 3.0 µM and 0.7 ± 0.04 for terfenadine block (n = 5); 1.1 ± 2.0 µM and 1.3 ± 0.09 for cisapride block (n = 5). Fits of I663P data yielded equivalent values of: 4.0 ± 4.0 µM and 0.4 ± 0.03 for terfenadine block (n = 4); 0.85 ± 0.2 µM and 0.7 ± 0.05 for cisapride block (n = 4).