Kuo C C, Bean B P
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115.
Mol Pharmacol. 1994 Oct;46(4):716-25.
The anticonvulsant phenytoin inhibited Na+ currents in rat hippocampal neurons with a potency that increased dramatically at depolarized holding potentials, suggesting weak binding to resting Na+ channels but tight binding to open or inactivated channels. Four different experimental measurements, i.e., steady block at different holding potentials, on and off kinetics at depolarized holding potentials, shifts in the inactivation curve, and dose-dependent slowing of recovery from inactivation, yielded an estimated Kd of approximately 7 microM for phenytoin binding to inactivated channels. Prolonged depolarizations of at least several seconds were necessary for significant block by therapeutic concentrations of phenytoin. The slow development of block does not reflect selective binding of phenytoin to slow inactivated states of the channel, because block developed faster and required less depolarized voltages than did slow inactivation. Instead, it appears that phenytoin binds tightly but slowly (approximately 10(4) M-1 sec-1) to fast inactivated states of the Na+ channels. This tight but slow binding may underlie the ability of phenytoin to disrupt epileptic discharges with minimal effects on normal firing patterns.
抗惊厥药苯妥英抑制大鼠海马神经元中的Na⁺电流，其效力在去极化钳制电位时显著增加，这表明它与静息Na⁺通道的结合较弱，但与开放或失活通道的结合紧密。四种不同的实验测量，即不同钳制电位下的稳态阻断、去极化钳制电位下的开启和关闭动力学、失活曲线的移位以及失活恢复的剂量依赖性减慢，得出苯妥英与失活通道结合的估计解离常数（Kd）约为7微摩尔。治疗浓度的苯妥英产生显著阻断需要至少数秒的长时间去极化。阻断的缓慢发展并不反映苯妥英对通道缓慢失活状态的选择性结合，因为与缓慢失活相比，阻断发展更快且所需的去极化电压更低。相反，苯妥英似乎与Na⁺通道的快速失活状态紧密但缓慢地结合（约10⁴ M⁻¹秒⁻¹）。这种紧密但缓慢的结合可能是苯妥英能够破坏癫痫放电而对正常放电模式影响最小的基础。
