Zhang Xiaoyu, Liu Yuqi, Xu Fangxia, Zhou Chengcheng, Lu Kaimei, Fang Bin, Wang Lijuan, Huang Lina, Xu Zifeng
Department of Anesthesiology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Anesthesiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Neural Regen Res. 2025 Sep 1;20(9):2682-2696. doi: 10.4103/NRR.NRR-D-23-01539. Epub 2024 Jun 3.
JOURNAL/nrgr/04.03/01300535-202509000-00029/figure1/v/2024-11-05T132919Z/r/image-tiff Protein arginine methyltransferase-6 participates in a range of biological functions, particularly RNA processing, transcription, chromatin remodeling, and endosomal trafficking. However, it remains unclear whether protein arginine methyltransferase-6 modifies neuropathic pain and, if so, what the mechanisms of this effect. In this study, protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model, chronic constriction injury model and bone cancer pain model, using immunohistochemistry, western blotting, immunoprecipitation, and label-free proteomic analysis. The results showed that protein arginine methyltransferase-6 mostly co-localized with β-tubulin III in the dorsal root ganglion, and that its expression decreased following spared nerve injury, chronic constriction injury and bone cancer pain. In addition, PRMT6 knockout (Prmt6-/-) mice exhibited pain hypersensitivity. Furthermore, the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression. Moreover, when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury, increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn, and the response to mechanical stimuli was enhanced. Mechanistically, protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F. Additionally, protein arginine methyltransferase-6-mediated modulation of heterogeneous nuclear ribonucleoprotein-F expression required amino acids 319 to 388, but not classical H3R2 methylation. These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target for the treatment of peripheral neuropathic pain.
《神经生长因子》/nrgr/04.03/01300535 - 202509000 - 00029/图1/v/2024 - 11 - 05T132919Z/图像 - tiff 蛋白质精氨酸甲基转移酶6参与一系列生物学功能，特别是RNA加工、转录、染色质重塑和内体运输。然而，蛋白质精氨酸甲基转移酶6是否会改变神经性疼痛，以及如果会，这种作用的机制是什么，目前仍不清楚。在本研究中，利用免疫组织化学、蛋白质免疫印迹法、免疫沉淀法和无标记蛋白质组学分析，在 spared 神经损伤模型、慢性压迫性损伤模型和骨癌疼痛模型中研究了蛋白质精氨酸甲基转移酶6的表达水平及其对神经性疼痛的影响。结果表明，蛋白质精氨酸甲基转移酶6在背根神经节中大多与β - 微管蛋白III共定位，并且在 spared 神经损伤、慢性压迫性损伤和骨癌疼痛后其表达降低。此外，PRMT6基因敲除（Prmt6 - / - ）小鼠表现出疼痛超敏反应。此外，通过阻止蛋白质精氨酸甲基转移酶6表达的降低，可减轻 spared 神经损伤诱导的对机械性疼痛的超敏反应的发展。而且，当在未发生 spared 神经损伤的小鼠背根神经节中下调蛋白质精氨酸甲基转移酶6的表达时，在同侧背角观察到磷酸化细胞外信号调节激酶水平升高，并且对机械刺激的反应增强。机制上，蛋白质精氨酸甲基转移酶6似乎通过调节异质性核核糖核蛋白 - F的表达来促成 spared 神经损伤诱导的神经性疼痛。此外，蛋白质精氨酸甲基转移酶6介导的异质性核核糖核蛋白 - F表达调节需要319至388位氨基酸，但不需要经典的H3R2甲基化。这些发现表明，蛋白质精氨酸甲基转移酶6是治疗周围神经性疼痛的潜在治疗靶点。
