Differential block of sodium and calcium channels by chlorpromazine in mouse neuroblastoma cells.
Differential block of sodium and calcium channels by chlorpromazine in mouse neuroblastoma cells.
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氯丙嗪对小鼠神经母细胞瘤细胞中钠和钙通道的差异阻断。
DOI：
10.1113/jphysiol.1990.sp017906
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发表时间：
1990
期刊：
影响因子：
--
通讯作者：
Narahashi,T
中科院分区：
文献类型：
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作者：
Ogata,N;Yoshii,M;Narahashi,T
1.采用全细胞膜片钳技术，在培养的小鼠神经母细胞瘤细胞（N1 E-115）中研究了氯丙嗪对电压激活钠和I型（瞬时）钙通道的影响。2.氯丙嗪（2 - 10 x 10（-6）M）以可逆和剂量依赖性方式阻断Ba 2+携带的钠通道电流和钙通道电流。3.阻断与钠和钙通道电流激活和失活的时间过程中的任何变化无关。4.在-120 mV的保持电位下测量的这些通道阻断的剂量-反应关系表明，钠和钙通道的结合化学计量比为1：1，表观解离常数分别为2.5 +/-10（-6）M和1.5 +/-10（-5）M。5.阻断依赖于两个通道电流的保持电位。当膜保持在-80 mV时，钠通道的表观解离常数降低至0.65 +/-10（-6）M。当膜保持在-60 mV时，钙通道的表观解离常数降低至3.2 +/-10（-6）M。6.暴露于1 x 10（-6）M-氯丙嗪后，钠通道的稳态失活曲线偏移12.4 +/-1.8 mV，变为更负的电位。暴露于1 x 10（-5）M-氯丙嗪后，钙通道的失活曲线也向更负的电位移动了15.4 +/-3.2 mV。这些结果表明，氯丙嗪对通道失活状态的亲和力大于静息状态。7.氯丙嗪引起钠通道电流的显著使用依赖性阻滞，如一系列去极化脉冲期间阻滞的累积增加所示。即使脉冲间期长达2 s，也观察到使用依赖性阻滞。8.另一方面，钙通道电流的阻断在一系列去极化脉冲期间没有显著积累，即使当以非常短的脉冲间间隔（200 ms）施加极长的（1 s）脉冲时也是如此。9.钠通道阻滞的显著使用依赖性是由于药物结合钠通道从失活中非常缓慢地重新启动，而钙通道阻滞缺乏使用依赖性是由于药物结合钙通道快速重新启动。（400字处截断摘要）
1. The effects of chlorpromazine on the voltage‐activated sodium and type I (transient) calcium channels were studied in cultured mouse neuroblastoma cells (N1E‐115) using the whole‐cell patch‐clamp technique. 2. Chlorpromazine (2‐10 x 10(‐6) M) blocked both the sodium channel current and the calcium channel current as carried by Ba2+ in a reversible and dose‐dependent manner. 3. The block was not associated with any change in the time course of the activation and inactivation of the sodium and calcium channel currents. 4. The dose‐response relationships for the block of these channels measured with a holding potential of ‐120 mV indicated a 1:1 binding stoichiometry with apparent dissociation constants of 2.5 +/‐ 10(‐6) M and 1.5 +/‐ 10(‐5) M for the sodium and calcium channels, respectively. 5. The block was dependent on the holding potential for both channel currents. The apparent dissociation constant for the sodium channel was decreased to 0.65 +/‐ 10(‐6) M when the membrane was held at ‐80 mV. The apparent dissociation constant for the calcium channel was decreased to 3.2 +/‐ 10(‐6) M when the membrane was held at ‐60 mV. 6. The steady‐state inactivation curve for the sodium channel was shifted by 12.4 +/‐ 1.8 mV to more negative potentials by exposure to 1 x 10(‐6) M‐chlorpromazine. The inactivation curve for the calcium channel was also shifted by 15.4 +/‐ 3.2 mV to more negative potentials by exposure to 1 x 10(‐5) M‐chlorpromazine. These results indicate a greater affinity of chlorpromazine for the inactivated state of the channels than for the resting state. 7. Chlorpromazine caused a marked use‐dependent block of the sodium channel current, as demonstrated by a cumulative increase of the block during a train of depolarizing pulses. The use‐dependent block was observed even with an interpulse interval as long as 2 s. 8. On the other hand, the block of the calcium channel current did not notably accumulate during a train of depolarizing pulses even when extremely prolonged (1 s) pulses were applied at a very short interpulse interval (200 ms). 9. The marked use dependence of the sodium channel block was due to a very slow repriming of the drug‐bound sodium channels from inactivation, whereas the lack of use dependence of the calcium channel block was due to a rapid repriming of the drug‐bound calcium channels.(ABSTRACT TRUNCATED AT 400 WORDS)