Sodium Channel Nav1.8 Underlies TTX-Resistant Axonal Action Potential Conduction in Somatosensory C-Fibers of Distal Cutaneous Nerves
Sodium Channel Nav1.8 Underlies TTX-Resistant Axonal Action Potential Conduction in Somatosensory C-Fibers of Distal Cutaneous Nerves
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DOI：
10.1523/jneurosci.3799-16.2017
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发表时间：
2017-05-17
影响因子：
5.3
通讯作者：
Ringkamp, Matthias
中科院分区：
文献类型：
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作者：
Klein, Amanda H.;Vyshnevska, Alina;Ringkamp, Matthias
电压门控钠（Na-V）通道负责初级传入内动作电位的起始和传导。在哺乳动物中识别的九种NaV通道亚型通常在功能上分为被纳摩尔浓度阻断的河豚毒素（TTX）敏感（TTX-s）通道（Na（V）1.1-Na（V）1.4，Na（V）1.6-Na（V）1.7）和被毫摩尔浓度抑制的TTX抗性（TTX-r）通道（Na（V）1.8和Na（V）1.9），其中Na（V）1.5具有中等毒素敏感性。对于小直径的初级传入神经元，目前还不清楚在何种程度上不同的Na-V通道亚型分布沿着其分叉轴突的外周和中央分支。为了确定TTX-s和TTX-r通道在不同轴突隔室中对动作电位传导的相对贡献，我们研究了TTX对小鼠和猪尾猴（Macacanemestrina）近端和远端周围神经节段和背根的C-纤维介导的复合动作电位（C-CAP）的影响。在小鼠和非人灵长类动物的背根和近端外周神经中，TTX将C-CAP振幅降低至基线的16%。相比之下，在猴和WT和Na（V）1.9（-/-）小鼠的远端外周分支中，>30%的C-CAP对TTX具有抗性。在Na（V）1.8（-/-）小鼠的神经中，TTX-r C-CAPs不能被检测到。这些数据表明，Na（V）1.8是TTX-r在体感C纤维远端轴突传导的主要亚型。此外，在C纤维轴突内Na（V）1.8的空间分布存在差异，在最远端轴突和末端区域中功能更突出。Na（V）1.8在远端轴突中的富集可能为治疗外周源性疼痛提供有用的靶点。
Voltage-gated sodium (Na-V) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine NaV channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (Na(V)1.1-Na(V)1.4, Na(V)1.6-Na(V)1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (Na(V)1.8 and Na(V)1.9) inhibited by millimolar concentrations, with Na(V)1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different Na-V channel isoforms are distributed along the peripheral and central branches of their bifurcated axons. To determine the relative contribution of TTX-s and TTX-r channels to action potential conduction in different axonal compartments, we investigated the effects of TTX on C-fiber-mediated compound action potentials (C-CAPs) of proximal and distal peripheral nerve segments and dorsal roots from mice and pigtail monkeys(Macacanemestrina). In the dorsal roots and proximal peripheral nerves of mice and nonhuman primates, TTX reduced the C-CAP amplitude to 16% of the baseline. In contrast, >30% of the C-CAP was resistant to TTX in distal peripheral branches of monkeys and WT and Na(V)1.9(-/-) mice. In nerves from Na(V)1.8(-/-) mice, TTX-r C-CAPs could not be detected. These data indicate that Na(V)1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of Na(V)1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of Na(V)1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin.