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

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

Author: Keliang CHEN ¹ ; Tao WANG ² ; Yong LI ¹ ; Jun WU ¹ ; Cheng-Xiao ZHAO ¹ ; Sheng LIU ¹ ; Fengrun SUN ² ; Yehong FANG ² ; Jiahuan HU ¹ ; Jinping HU ¹ ; Chong-Jing ZHANG ¹ ; Haibo YU ¹ ; Chao MA ² ; Shi-Shan YU ¹
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1. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
2. Institute of Basic Medical Sciences, Neuroscience Center, Chinese Academy of Medical Sciences, Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
Publication Type:Journal Article
Keywords: Cav2.2; NSF; Natural product; Neuropathic pain; Rhodojaponin VI
From: Acta Pharmaceutica Sinica B 2023;13(3):1326-1336
CountryChina
Language:English
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.