Delicate effects of drug structure and local conformation around Y1618 on the slowing of the macroscopic current decay in the Y1618K mutant channel. (A) The experiments and plots are done in the Y1618K mutant channel with the same methods described in Fig. 5, except that different concentrations of different anticonvulsants were applied. The macroscopic currents recorded in the presence (red lines) and absence (black lines) of drugs are superimposed. The slowing effects on the macroscopic current decay by 100 μM carbamazepine, 100 μM phenytoin, and 300 μM diclofenac are discernible. However, lamotrigine, even at 1 mM, only has a negligible effect on the decay. The dotted line indicates zero current level. The relative decay rates (the decay rate in drug relative to that in control) in the Y1618K mutant channel are shown in the bar graph for different concentrations of different drugs (n = 3–9). (B) The effect of concomitant mutations of another residue in the D4S3-4 linker or in the D4S4-5 linker on the slowed macroscopic current decay by carbamazepine in the Y1618K mutant channel. The macroscopic currents recorded in the presence (red lines) and absence (black lines) of 300 μM carbamazepine are superimposed. In the F1619K single-mutant and the Y1618K plus F1619K, K1617A, E1616K, or R1626 double-mutant channels, 300 μM carbamazepine shows no slowing effect on the macroscopic current decay. On the other hand, in the Y1618K/F1651A double-mutant channel, carbamazepine still slows the development of the partially impaired inactivation (ascribable to F1651A mutation). In this case, however, carbamazepine still helps to stabilize inactivation and reduces the sustained current at the end of a prolonged depolarizing pulse (e.g., 2 s; the inset figure). The dotted line indicates zero current level. (Right) The macroscopic decay rate in 300 μM carbamazepine is normalized to that in control to obtain the relative decay rate in different mutant channels (n = 3–9).