Tetrodotoxin-Resistant Sodium Channels in Sensory Neurons Generate Slow Resurgent Currents That Are Enhanced by Inflammatory Mediators
Tetrodotoxin-Resistant Sodium Channels in Sensory Neurons Generate Slow Resurgent Currents That Are Enhanced by Inflammatory Mediators
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DOI：
10.1523/jneurosci.5011-13.2014
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发表时间：
2014-05-21
影响因子：
5.3
通讯作者：
Cummins, Theodore R.
中科院分区：
文献类型：
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作者：
Tan, Zhi-Yong;Piekarz, Andrew D.;Cummins, Theodore R.
复苏的钠电流有助于动作电位的再生和增强神经元的兴奋性。河豚毒素敏感性（TTX-S）复活电流已在许多不同的神经元群体中被描述，包括小脑和背根神经节（DRG）神经元。在大多数情况下，钠通道Nav1.6是这些TTX-S复活电流的主要贡献者。在这里，我们报告了一种新的TTX-R的复苏电流记录从大鼠DRG神经元。TTX-R复活电流在许多方面类似于经典TTX-S复活电流，但不是全部。与TTX-S复活电流一样，它们被膜复极化激活，被利多卡因抑制，并被β 4钠通道亚单位胞内结构域的肽模拟物增强。然而，TTX-R复活电流表现出慢得多的动力学，发生在更多的去极化电压，并对Nav1.8阻断剂A803467敏感。此外，来自大鼠DRG裂解物的免疫共沉淀实验表明，在DRG神经元中，内源性钠通道β 4亚基与Nav1.8相关。这些结果表明，在DRG神经元中慢TTX-R复活电流是由Nav1.8介导的，并且由TTX-S复活电流的相同机制产生。我们还发现，在DRG神经元的TTX-S和TTX-R复苏电流增强炎症介质。此外，β 4肽在TTX存在下增加小DRG神经元的兴奋性。我们建议，这些缓慢的TTX-R复苏电流有助于膜的伤害性DRG神经元在正常条件下的兴奋性和增强这两种类型的复苏电流的炎症介质可能有助于与炎性疼痛相关的感觉神经元的超兴奋性。
Resurgent sodium currents contribute to the regeneration of action potentials and enhanced neuronal excitability. Tetrodotoxin-sensitive (TTX-S) resurgent currents have been described in many different neuron populations, including cerebellar and dorsal root ganglia (DRG) neurons. In most cases, sodium channel Nav1.6 is the major contributor to these TTX-S resurgent currents. Here we report a novel TTX-resistant (TTX-R) resurgent current recorded from rat DRG neurons. The TTX-R resurgent currents are similar to classic TTX-S resurgent currents in many respects, but not all. As with TTX-S resurgent currents, they are activated by membrane repolarization, inhibited by lidocaine, and enhanced by a peptide-mimetic of the beta 4 sodium channel subunit intracellular domain. However, the TTX-R resurgent currents exhibit much slower kinetics, occur at more depolarized voltages, and are sensitive to the Nav1.8 blocker A803467. Moreover, coimmunoprecipitation experiments from rat DRG lysates indicate the endogenous sodium channel beta 4 subunits associate with Nav1.8 in DRG neurons. These results suggest that slow TTX-R resurgent currents in DRG neurons are mediated by Nav1.8 and are generated by the same mechanism underlying TTX-S resurgent currents. We also show that both TTX-S and TTX-R resurgent currents in DRG neurons are enhanced by inflammatory mediators. Furthermore, the beta 4 peptide increased excitability of small DRG neurons in the presence of TTX. We propose that these slow TTX-R resurgent currents contribute to the membrane excitability of nociceptive DRG neurons under normal conditions and that enhancement of both types of resurgent currents by inflammatory mediators could contribute to sensory neuronal hyperexcitability associated with inflammatory pain.