Rhodojaponin VI indirectly targets Cav2.2 channels via N-ethylmaleimide-sensitive fusion protein to alleviate neuropathic pain

IF 14.7 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Keliang Chen , Tao Wang , Yong Li , Jun Wu , Cheng-Xiao Zhao , Sheng Liu , Fengrun Sun , Yehong Fang , Jiahuan Hu , Jinping Hu , Chong-Jing Zhang , Haibo Yu , Chao Ma , Shi-Shan Yu
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引用次数: 4

Abstract

Neuropathic pain is a chronic disease that severely afflicts the life and emotional status of patients, but currently available treatments are often ineffective. Novel therapeutic targets for the alleviation of neuropathic pain are urgently needed. Rhodojaponin VI, a grayanotoxin from Rhododendron molle, showed remarkable antinociceptive efficacy in models of neuropathic pain, but its biotargets and mechanisms are unknown. Given the reversible action of rhodojaponin VI and the narrow range over which its structure can be modified, we perforwmed thermal proteome profiling of the rat dorsal root ganglion to determine the protein target of rhodojaponin VI. N-Ethylmaleimide-sensitive fusion (NSF) was confirmed as the key target of rhodojaponin VI through biological and biophysical experiments. Functional validation showed for the first time that NSF facilitated trafficking of the Cav2.2 channel to induce an increase in Ca2+ current intensity, whereas rhodojaponin VI reversed the effects of NSF. In conclusion, rhodojaponin VI represents a unique class of analgesic natural products targeting Cav2.2 channels via NSF.

Abstract Image

罗多焦蛋白VI通过N-乙基马来酰亚胺敏感融合蛋白间接靶向Cav2.2通道,减轻神经性疼痛
神经性疼痛是一种严重折磨患者生活和情绪状态的慢性疾病,但目前可用的治疗方法往往无效。迫切需要用于减轻神经性疼痛的新的治疗靶点。杜鹃花素VI是一种从毛杜鹃中提取的灰安毒素,在神经性疼痛模型中表现出显著的镇痛作用,但其生物靶点和机制尚不清楚。鉴于刺参蛋白VI的可逆作用及其结构修饰范围较窄,我们对大鼠背根神经节进行了热蛋白质组分析,以确定刺参蛋白的蛋白质靶标。通过生物学和生物物理实验,N-乙基马来酰亚胺敏感融合(NSF)被确认为刺参蛋白Ⅵ的关键靶标。功能验证首次表明,NSF促进了Cav2.2通道的运输,以诱导Ca2+电流强度的增加,而洋刺参VI逆转了NSF的作用。总之,日本杜鹃花素VI代表了一类独特的天然镇痛产物,通过NSF靶向Cav2.2通道。
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来源期刊
Acta Pharmaceutica Sinica. B
Acta Pharmaceutica Sinica. B Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
22.40
自引率
5.50%
发文量
1051
审稿时长
19 weeks
期刊介绍: The Journal of the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association oversees the peer review process for Acta Pharmaceutica Sinica. B (APSB). Published monthly in English, APSB is dedicated to disseminating significant original research articles, rapid communications, and high-quality reviews that highlight recent advances across various pharmaceutical sciences domains. These encompass pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis, and pharmacokinetics. A part of the Acta Pharmaceutica Sinica series, established in 1953 and indexed in prominent databases like Chemical Abstracts, Index Medicus, SciFinder Scholar, Biological Abstracts, International Pharmaceutical Abstracts, Cambridge Scientific Abstracts, and Current Bibliography on Science and Technology, APSB is sponsored by the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association. Its production and hosting are facilitated by Elsevier B.V. This collaborative effort ensures APSB's commitment to delivering valuable contributions to the pharmaceutical sciences community.
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