Inflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity.
Inflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity.
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DOI：
10.1073/pnas.2215417120
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发表时间：
2023-03-14
影响因子：
11.1
通讯作者：
Waxman, Stephen G.
中科院分区：
文献类型：
--
作者：
Higerd-Rusli, Grant P.;Tyagi, Sidharth;Baker, Christopher A.;Liu, Shujun;Dib-Hajj, Fadia B.;Dib-Hajj, Sulayman D.;Waxman, Stephen G.
疼痛的负担是巨大的，而目前的治疗方法往往无效且容易上瘾。痛觉神经元的活动由促兴奋（NaV）通道促进，由抗兴奋电压门控钾（KV）通道抑制。NaV1.7是非成瘾性疼痛治疗的一个有希望的靶点，调节其向轴突膜的转运是一种潜在的治疗策略。然而，这种方法需要确定与其他通道（如KV7.2）不同的调节NaV1.7通道贩运的机制。我们研究了活神经元的通道运输，发现炎症介质（IM）通过囊泡负载和轴突运输增加NaV1.7表面密度，而不增加KV7.2运输。因此，NaV1.7的转运受到炎症的不同调节，从而促进疼痛，可能具有靶向治疗作用。炎症通过改变伤害感受器中离子电流的平衡而引起疼痛，从而导致过度兴奋。质膜内离子通道的集合受生物发生、运输和降解等过程的调控。因此，离子通道运输的改变可能影响兴奋性。钠通道NaV1.7和钾通道KV7.2分别促进和抑制伤害感受器的兴奋性。我们使用活细胞成像来研究炎症介质（IM）通过转录、囊泡负载、轴突运输、胞吐和内吞作用调节轴突表面这些通道丰度的机制。炎症介质诱导远端轴突nav1.7依赖性活性增加。此外，炎症增加了轴突表面NaV1.7的丰度，而不是KV7.2的丰度，这是通过选择性地增加通道负载进入顺行运输囊泡和插入膜，而不影响逆行运输。这些结果揭示了炎症性疼痛的细胞生物学机制，并提示NaV1.7转运是潜在的治疗靶点。
The burden of pain is immense, and current treatments are often ineffective and addictive. Activity in pain-sensing neurons is promoted by proexcitatory (NaV) channels and inhibited by antiexcitatory voltage-gated potassium (KV) channels. NaV1.7 is a promising target for nonaddictive pain treatment, and modulating its transport to axonal membranes is a potential therapeutic strategy. However, this approach requires identifying mechanisms which differentially regulate trafficking of NaV1.7 channels over other channels such as KV7.2. We investigated channel trafficking in live neurons and found that inflammatory mediators (IM) increase NaV1.7 surface density through vesicular loading and axonal transport, without similarly increasing KV7.2 transport. Thus, trafficking of NaV1.7 is differentially regulated by inflammation to promote pain and might be targeted therapeutically. Inflammation causes pain by shifting the balance of ionic currents in nociceptors toward depolarization, leading to hyperexcitability. The ensemble of ion channels within the plasma membrane is regulated by processes including biogenesis, transport, and degradation. Thus, alterations in ion channel trafficking may influence excitability. Sodium channel NaV1.7 and potassium channel KV7.2 promote and oppose excitability in nociceptors, respectively. We used live-cell imaging to investigate mechanisms by which inflammatory mediators (IM) modulate the abundance of these channels at axonal surfaces through transcription, vesicular loading, axonal transport, exocytosis, and endocytosis. Inflammatory mediators induced a NaV1.7-dependent increase in activity in distal axons. Further, inflammation increased the abundance of NaV1.7, but not of KV7.2, at axonal surfaces by selectively increasing channel loading into anterograde transport vesicles and insertion at the membrane, without affecting retrograde transport. These results uncover a cell biological mechanism for inflammatory pain and suggest NaV1.7 trafficking as a potential therapeutic target.
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DOI：
10.1093/brain/awab113
发表时间：
2021-07-28
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Akin EJ;Alsaloum M;Higerd GP;Liu S;Zhao P;Dib-Hajj FB;Waxman SG;Dib-Hajj SD
通讯作者：
Dib-Hajj SD
影响因子：
5.3
作者：
Higerd-Rusli, Grant P.;Alsaloum, Matthew;Waxman, Stephen G.
通讯作者：
Waxman, Stephen G.
影响因子：
--
作者：
Baldini, Angee;Von Korff, Michael;Lin, Elizabeth H B
通讯作者：
Lin, Elizabeth H B
影响因子：
5.5
作者：
HODGKIN, AL;HUXLEY, AF
通讯作者：
HUXLEY, AF
影响因子：
7.7
作者：
Jakobs, Maximilian A. H.;Dimitracopoulos, Andrea;Franze, Kristian
通讯作者：
Franze, Kristian