Slow binding of phenytoin to inactivated sodium channels in rat hippocampal neurons.
Slow binding of phenytoin to inactivated sodium channels in rat hippocampal neurons.
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发表时间：
1994-10
影响因子：
3.6
通讯作者：
Chung-Chin Kuo;Bruce P. Bean
中科院分区：
文献类型：
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作者：
Chung-Chin Kuo;Bruce P. Bean
抗惊厥药苯妥英钠对大鼠海马神经元Na+电流的抑制作用在去极化保持电位时显著增加，提示与静息Na+通道的结合较弱，而与开放或非激活的通道结合紧密。四种不同的实验测量，即在不同保持电位下的稳定阻断，在去极化保持电位下的通断动力学，失活曲线的移动，以及从失活恢复的剂量依赖的减慢，得到了苯妥英与失活通道结合的估计Kd值约为7微米。治疗浓度的苯妥英钠需要至少几秒钟的长时间去极化才能显著阻断。阻断的缓慢发展并不反映苯妥英选择性地结合到通道的缓慢失活状态，因为与缓慢失活相比，阻断发展得更快，需要更少的去极化电压。相反，苯妥英似乎紧密但缓慢地结合到钠离子通道的快速失活状态(约10(4)M-1秒-1)。这种紧密但缓慢的结合可能是苯妥英干扰癫痫放电而对正常放电模式影响最小的能力的基础。
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.