Cumulative inhibition of voltage-gated Na
+ channel current (
INa) caused by high-frequency depolarization plays a critical role in regulating electrical activity in excitable cells. As discussed in this review paper, exposure to certain small-molecule modulators can perturb
INa during
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Cumulative inhibition of voltage-gated Na
+ channel current (
INa) caused by high-frequency depolarization plays a critical role in regulating electrical activity in excitable cells. As discussed in this review paper, exposure to certain small-molecule modulators can perturb
INa during high-frequency stimulation, influencing the extent of cumulative inhibition and electrical excitability in excitable cells. Carbamazepine differentially suppressed transient or peak (
INa(T)) and late (
INa(L)) components of
INa. Moreover, the cumulative inhibition of
INa(T) during pulse-train stimulation at 40 Hz was enhanced by lacosamide. GV-58 was noted to exert stimulatory effect on
INa(T) and
INa(L). This stimulated
INa was not countered by ω-conotoxin MVIID but was effectively reversed by ranolazine. GV-58′s exposure can slow down
INa inactivation elicited during pulse-train stimulation. Lacosamide directly inhibited
INa magnitude as well as promoted this cumulative inhibition of
INa during pulse-train stimuli. Mirogabalin depressed
INa magnitude as well as modulated frequency dependence of the current. Phenobarbital can directly modulate both the magnitude and frequency dependence of ionic currents, including
INa. Previous investigations have shown that exposure to small-molecule modulators can perturb
INa under conditions of high-frequency stimulation. This ionic mechanism plays a crucial role in modulating membrane excitability, hereby supporting the validity of these findings.
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