电压门控钠离子通道是可兴奋细胞产生动作电位的基础，其亚型1.8（Nav1.8）选择性分布于外周神经系统，并对炎性痛和神经病理性痛有重要贡献。之前的研究显示，Nav1.8主要定位于背根神经节（DRG）神经元的细胞质内，外周炎症和神经损伤时聚集到坐骨神经中，但是Nav1.8在神经纤维中发生聚集的分子机制及生理病理意义并不十分清楚。

　　11月6日，《神经科学杂志》发表了中科院上海生科院生物化学与细胞生物学研究所鲍岚研究组的研究工作。该项工作中，博士研究生苏园园等发现动力蛋白KIF5B可以促进Nav1.8由胞浆到细胞膜的正向运输和向轴突的轴浆运输。在完全弗氏佐剂诱导的炎症模型中，KIF5和Nav1.8均能在坐骨神经中发生聚集。当DRG中KIF5亚型KIF5B表达降低时，Nav1.8的电流密度也随之下降，而KIF5B过表达可以增加Nav1.8的膜上表达量和电流密度，并且Brefeldin A处理可以阻断这种增加，说明KIF5B促进了Nav1.8的正向运输。

    免疫共沉淀实验显示，KIF5B的511-620区段可以与Nav1.8的N端相互作用。进一步的研究发现，在培养的DRG神经元中过表达KIF5B可以促进Nav1.8的轴浆运输，导致Nav1.8在轴突中发生聚集，从而提高了神经元轴突的兴奋性。因此，KIF5B对于Nav1.8的正向运输是必需的，这为病理情况下Nav1.8在神经纤维中发生聚集提供了一种可能的分子机制。此项研究有助于深入理解生理及病理情况下Nav1.8运输和功能的调控机理。

　　该工作得到了中国科学院、国家自然科学基金、科技部蛋白质重大研究计划等项目的资助。

原文摘要：

KIF5B Promotes the Forward Transport and Axonal Function of the Voltage-Gated Sodium Channel Nav1.8.

Nav1.8 is a tetrodotoxin-resistant voltage-gated sodium channel selectively expressed in primary sensory neurons. Peripheral inflammation and nerve injury induce Nav1.8 accumulation in peripheral nerves. However, the mechanisms and related significance of channel accumulation in nerves remains unclear. Here we report that KIF5B promotes the forward transport of Nav1.8 to the plasma membrane and axons in dorsal root ganglion (DRG) neurons of the rat. In peripheral inflammation induced through the intraplantar injection of complete Freund's adjuvant, increased KIF5 and Nav1.8 accumulation were observed in the sciatic nerve. The knock-down of KIF5B, a highly expressed member of the KIF5 family in DRGs, reduced the current density of Nav1.8 in both cultured DRG neurons and ND7-23 cells. Overexpression of KIF5B in ND7-23 cells increased the current density and surface expression of Nav1.8, which were abolished through brefeldin A treatment, whereas the increases were lost in KIF5B mutants defective in ATP hydrolysis or cargo binding. Overexpression of KIF5B also decreased the proteasome-associated degradation of Nav1.8. In addition, coimmunoprecipitation experiments showed interactions between the N terminus of Nav1.8 and the 511-620 aa sequence in the stalk domain of KIF5B. Furthermore, KIF5B increased Nav1.8 accumulation, Nav1.8 current, and neuronal excitability detected in the axons of cultured DRG neurons, which were completely abolished by the disruption of interactions between KIF5B and the N terminus of Nav1.8. Therefore, our results reveal that KIF5B is required for the forward transport and axonal function of Nav1.8, suggesting a mechanism for axonal accumulation of Nav1.8 in inflammatory pain.

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