Figure 4. Selective elimination of M-current (I_M) and H-current (I_h) by the ion channel blockers XE991 and ZD7288.

Whole-cell voltage-clamp recordings from CA1 pyramidal cells bathed in 1 μm TTX to block Na⁺ channels. A1, typical example showing that XE991, but not ZD7288, blocked I_M. I_M was recorded by giving 4 s-long -20 mV voltage-clamp steps to -50 mV from a holding potential of -30 mV. M-channel closure was seen as a slow inward relaxation (tail current) after stepping to -50 mV, and M-channel reopening as a slow outward relaxation after stepping back to -30 mV. Bath application of 10 μm ZD7288 had no detectible effect, whereas subsequent application of 10 μm XE911 fully blocked I_M, abolishing the relaxations and causing an inward shift of the holding current. A2, the XE991-sensitive current, calculated by subtracting the current traces before and after XE991, at an expanded time scale. Note the larger instantaneous jump in the current when stepping from -30 to -50 mV (when most M-channels are open), compared to stepping from -50 to -30 mV (when most M-channels are closed). The example shown in A2 is taken form a different cell than A1 because an A-current evoked by the step to -30 mV partly masked the time course of M-current opening in A1. B1, ZD7288, but not XE991, blocked I_h. The cell was maintained at -70 mV, and stepped to -100 mV for 1 s. I_h activation and deactivation were seen as slow inward and outward relaxations at the beginning and end of the step, respectively. I_h was highly resistant to 10 μm XE991, but was fully blocked by subsequent application of 10 μm ZD7288. B2, the ZD7288-sensitive current, calculated by subtracting the current traces before and after ZD7288, shown at an expanded time scale. C, XE991-sensitive difference current amplitude, obtained by subtraction of currents before and after the application of 10 μm XE991, plotted as a function of membrane potential (V). D, ZD7288-sensitive difference current amplitude, obtained by subtraction of currents before and after the application of 10 μm ZD7288, plotted as a function of membrane potential (V). In C and D, the difference currents were measured at the end of the negative-going voltage step (cf. panels A2 and B2). TTX (1 μm) was applied throughout all experiments (A-D) to block Na⁺ channels.