Segal M M, Douglas A F
Department of Neurology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Neurophysiol. 1997 Jun;77(6):3021-34. doi: 10.1152/jn.1997.77.6.3021.
Late openings of sodium channels were observed in outside-out patch recordings from hippocampal neurons in culture. In previous studies of such neurons, a persistent sodium current appeared to underlie the ictal epileptiform activity. All the channel currents were blocked by tetrodotoxin. In addition to the transient openings of sodium channels making up the peak sodium current, there were two types of late channel openings: brief late and burst openings. These late channel openings occurred throughout voltage pulses that lasted 750 ms, producing a persistent sodium current. At -30 mV, this current was 0.4% of the peak current. The late channel openings occurred throughout the physiological range of trans-membrane voltages. The anticonvulsant phenytoin reduced the late channel openings more than the peak currents. The effect on the persistent current was greatest at more depolarized voltages, whereas the effect on peak currents was not substantially voltage dependent. In the presence of 60 microM phenytoin, peak sodium currents at -30 mV were 40-41% of control, as calculated using different methods of analysis. Late currents were 22-24% of control. Phenytoin primarily decreased the number of channel openings, with less effect on the duration of channel openings and no effect on open channel current. This set of findings is consistent with models in which phenytoin binds to the inactivated state of the channel. The preferential effect of phenytoin on the persistent sodium current suggests that an important pharmacological mechanism for a sodium channel anticonvulsant is to reduce late openings of sodium channels, rather than reducing all sodium channel openings. We hypothesize that pharmacological interventions that are most selective in reducing late openings of sodium channels, while leaving early channel openings relatively intact, will be those that produce an anticonvulsant effect while interfering minimally with normal function.
在培养的海马神经元的外向膜片钳记录中观察到钠通道的延迟开放。在先前对这类神经元的研究中，一种持续性钠电流似乎是发作期癫痫样活动的基础。所有通道电流均被河豚毒素阻断。除了构成钠电流峰值的钠通道瞬时开放外，还有两种类型的延迟通道开放：短暂延迟开放和爆发性开放。这些延迟通道开放发生在持续750毫秒的电压脉冲期间，产生持续性钠电流。在-30 mV时，该电流为峰值电流的0.4%。延迟通道开放发生在跨膜电压的生理范围内。抗惊厥药物苯妥英对延迟通道开放的抑制作用比对峰值电流的抑制作用更大。对持续性电流的影响在去极化程度更高的电压下最大，而对峰值电流的影响基本上不依赖于电压。在存在60 microM苯妥英的情况下，使用不同分析方法计算得出，在-30 mV时的峰值钠电流为对照值的40 - 41%。延迟电流为对照值的22 - 24%。苯妥英主要减少通道开放的数量，对通道开放的持续时间影响较小，对开放通道电流没有影响。这一系列发现与苯妥英与通道失活状态结合的模型一致。苯妥英对持续性钠电流的优先作用表明，钠通道抗惊厥药物的一个重要药理机制是减少钠通道的延迟开放，而不是减少所有钠通道开放。我们假设对减少钠通道延迟开放最具选择性，同时使早期通道开放相对完整的药理干预措施，将是那些在最小程度干扰正常功能时产生抗惊厥作用的措施。
