Role of Tetrodotoxin-Resistant Na+ Current Slow Inactivation in Adaptation of Action Potential Firing in Small-Diameter Dorsal Root Ganglion Neurons
Role of Tetrodotoxin-Resistant Na+ Current Slow Inactivation in Adaptation of Action Potential Firing in Small-Diameter Dorsal Root Ganglion Neurons
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DOI：
10.1523/jneurosci.23-32-10338.2003
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发表时间：
2003-11
期刊：
影响因子：
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通讯作者：
Nathaniel T. Blair;B. Bean
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文献类型：
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作者：
Nathaniel T. Blair;B. Bean
当急性分离的小直径背根神经节（DRG）神经元刺激与重复电流注射或辣椒素的长期应用，他们的动作电位放电迅速适应。由于TTX-R钠电流在这些假定的伤害性感受器中产生大部分的去极化电流，我们研究了TTX-R钠通道失活在产生适应中的可能作用。在电压钳下，短去极化引起的TTX-R电流在低至1 Hz的频率下显示出强烈的使用依赖性，尽管从快速失活的恢复在10-30 msec内完成。这种使用依赖性减少是TTX-R钠通道进入缓慢失活状态的结果。缓慢失活更有效地产生稳定的去极化比通过开放状态的循环通道。缓慢失活具有陡峭的电压依赖性，Boltzmann斜率因子为5 mV，中点接近-45 mV（5秒调节脉冲），完全性为-93%至-20 mV。进入的时间常数（± 200 msec）与-20 mV至+60 mV的电压无关，而恢复动力学具有中度电压依赖性（时间常数，-60 mV时为± 1.5 sec，-100 mV时为± 0.5 sec）。使用预先记录的电流钳反应辣椒素作为电压钳命令波形，我们发现，自适应发射发生的时间过程类似的发展缓慢失活。因此，TTX-R钠电流的缓慢失活限制了小DRG细胞响应维持刺激的放电持续时间，并可能导致化学和电刺激之间的交叉脱敏。
When acutely dissociated small-diameter dorsal root ganglion (DRG) neurons were stimulated with repeated current injections or prolonged application of capsaicin, their action potential firing quickly adapted. Because TTX-resistant (TTX-R) sodium current in these presumptive nociceptors generates a large fraction of depolarizing current during the action potential, we examined the possible role of inactivation of TTX-R sodium channels in producing adaptation. Under voltage clamp, TTX-R current elicited by short depolarizations showed strong use dependence at frequencies as low as 1 Hz, although recovery from fast inactivation was complete in ∼10-30 msec. This use-dependent reduction was the result of the entry of TTX-R sodium channels into slow inactivated states. Slow inactivation was more effectively produced by steady depolarization than by cycling channels through open states. Slow inactivation was steeply voltage dependent, with a Boltzmann slope factor of 5 mV, a midpoint near -45 mV (5 sec conditioning pulses), and completeness of ∼93% positive to -20 mV. The time constant for entry (∼200 msec) was independent of voltage from -20 mV to +60 mV, whereas recovery kinetics were moderately voltage dependent (time constant, ∼1.5 sec at -60 mV and ∼0.5 sec at -100 mV). Using a prerecorded current-clamp response to capsaicin as a voltage-clamp command waveform, we found that adaptation of firing occurred with a time course similar to that of development of slow inactivation. Thus, slow inactivation of the TTX-R sodium current limits the duration of small DRG cell firing in response to maintained stimuli and may contribute to cross desensitization between chemical and electrical stimuli.