Paclitaxel increases axonal localization and vesicular trafficking of Nav1.7.
Paclitaxel increases axonal localization and vesicular trafficking of Nav1.7.
复制标题
DOI：
10.1093/brain/awab113
复制
发表时间：
2021-07-28
期刊：
影响因子：
--
通讯作者：
Dib-Hajj SD
中科院分区：
文献类型：
--
作者：
Akin EJ;Alsaloum M;Higerd GP;Liu S;Zhao P;Dib-Hajj FB;Waxman SG;Dib-Hajj SD
请参阅Silagi和Segal（doi：）对本文的科学评论。化疗药物紫杉醇诱导感觉神经元中Nav1.7通道表达增加，增强其兴奋性。Akin等人使用实时成像来可视化暴露于紫杉醇后感觉轴突中Nav1.7通道的运输和表面定位，并揭示炎症在该过程中的作用。微管稳定化疗药物紫杉醇（PTX）导致剂量限制性化疗诱导的周围神经病变（CIPN），这通常伴有疼痛。PTX的多方面作用包括增加大鼠和人类感觉神经元中钠通道Nav1.7的表达，增强其兴奋性。然而，这种增加的Nav1.7表达的机制尚未被探索，PTX治疗对感觉轴突中Nav1.7通道的运输和定位的动力学的影响迄今为止还不可能研究。在这项研究中，我们使用了一种最近开发的实时成像方法，可以可视化Nav1.7表面通道和感觉神经元中的长距离轴突囊泡运输，以填补这一基本知识空白。我们证明了PTX对感觉轴突中Nav1.7的囊泡运输和实时膜定位的浓度和时间依赖性影响。低浓度的PTX增加表面通道表达和囊泡通量（每个轴突的囊泡数目）。相比之下，用较高浓度的PTX处理降低囊泡通量。有趣的是，两种浓度的PTX的囊泡速度增加。PTX处理后，背根神经节神经元内源性Nav1.7 mRNA水平和电流密度增加。然而，通过用Halo-tag Nav1.7转染背根神经节神经元产生的电流在暴露于PTX后没有增加。综上所述，这表明我们在用PTX处理后通过在转染的背根神经节神经元中的活体成像观察到的Halo-Nav 1.7的增加的运输和表面定位可能不依赖于Nav 1. 7通道池的增加。暴露于炎症介质以模拟化疗期间观察到的炎症状况后，对于低浓度和高浓度的PTX，Nav1.7表面水平和囊泡转运均增加。总体而言，我们的研究结果表明，PTX治疗增加了背根神经节神经元中功能性内源性Nav1.7通道的水平，并增强了Nav1.7在感觉轴突中的运输和表面分布，其结果取决于炎症环境的存在，为CIPN中初级传入和疼痛的兴奋性增加提供了机制解释。
See Silagi and Segal (doi:) for a scientific commentary on this article. The chemotherapy drug paclitaxel induces an increase in Nav1.7 channel expression in sensory neurons, enhancing their excitability. Akin et al. use live imaging to visualize trafficking and surface localization of Nav1.7 channels in sensory axons after exposure to paclitaxel, and reveal a role for inflammation in this process. The microtubule-stabilizing chemotherapy drug paclitaxel (PTX) causes dose-limiting chemotherapy-induced peripheral neuropathy (CIPN), which is often accompanied by pain. Among the multifaceted effects of PTX is an increased expression of sodium channel Nav1.7 in rat and human sensory neurons, enhancing their excitability. However, the mechanisms underlying this increased Nav1.7 expression have not been explored, and the effects of PTX treatment on the dynamics of trafficking and localization of Nav1.7 channels in sensory axons have not been possible to investigate to date. In this study we used a recently developed live imaging approach that allows visualization of Nav1.7 surface channels and long-distance axonal vesicular transport in sensory neurons to fill this basic knowledge gap. We demonstrate concentration and time-dependent effects of PTX on vesicular trafficking and membrane localization of Nav1.7 in real-time in sensory axons. Low concentrations of PTX increase surface channel expression and vesicular flux (number of vesicles per axon). By contrast, treatment with a higher concentration of PTX decreases vesicular flux. Interestingly, vesicular velocity is increased for both concentrations of PTX. Treatment with PTX increased levels of endogenous Nav1.7 mRNA and current density in dorsal root ganglion neurons. However, the current produced by transfection of dorsal root ganglion neurons with Halo-tag Nav1.7 was not increased after exposure to PTX. Taken together, this suggests that the increased trafficking and surface localization of Halo-Nav1.7 that we observed by live imaging in transfected dorsal root ganglion neurons after treatment with PTX might be independent of an increased pool of Nav1.7 channels. After exposure to inflammatory mediators to mimic the inflammatory condition seen during chemotherapy, both Nav1.7 surface levels and vesicular transport are increased for both low and high concentrations of PTX. Overall, our results show that PTX treatment increases levels of functional endogenous Nav1.7 channels in dorsal root ganglion neurons and enhances trafficking and surface distribution of Nav1.7 in sensory axons, with outcomes that depend on the presence of an inflammatory milieu, providing a mechanistic explanation for increased excitability of primary afferents and pain in CIPN.
登录
查看更多内容
影响因子：
5.3
作者：
Lehmann HC;Staff NP;Hoke A
通讯作者：
Hoke A
影响因子：
4.5
作者：
Materazzi, Serena;Fusi, Camilla;Nassini, Romina
通讯作者：
Nassini, Romina
影响因子：
7.7
作者：
Jakobs, Maximilian A. H.;Dimitracopoulos, Andrea;Franze, Kristian
通讯作者：
Franze, Kristian
影响因子：
14.8
作者：
Dib-Hajj, Sulayman D.;Choi, Jin Sung;Waxman, Stephen G.
通讯作者：
Waxman, Stephen G.
紫杉醇的神经毒性机制是远端轴突局部的，独立于运输缺陷。
影响因子：
5.3
作者：
Gornstein EL;Schwarz TL
通讯作者：
Schwarz TL