Protein disulfide isomerase modulation of TRPV1 controls heat hyperalgesia in chronic pain

• Published in: Cell reports (Cambridge) Vol. 39; no. 1; p. 110625
• Main Authors: Zhang, Yongxue, Miao, Qi, Shi, Sai, Hao, Han, Li, Xinmeng, Pu, Zeyao, Yang, Yakun, An, Hailong, Zhang, Wei, Kong, Youzhen, Pang, Xu, Gu, Cunyang, Gamper, Nikita, Wu, Yi, Zhang, Hailin, Du, Xiaona
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.04.2022; Elsevier
• Subjects: Animals; Chronic Pain; CP: Neuroscience; cysteine oxidation; DRG; Hot Temperature; Humans; Hyperalgesia - metabolism; Mice; Oxidation-Reduction; PDI; Protein Disulfide-Isomerases - metabolism; Protein Folding; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; TRPV1; DRG; chronic pain; TRPV1; PDI; CP: Neuroscience; cysteine oxidation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110625

Protein disulfide isomerase (PDI) plays a key role in maintaining cellular homeostasis by mediating protein folding via catalyzing disulfide bond formation, breakage, and rearrangement in the endoplasmic reticulum. Increasing evidence suggests that PDI can be a potential treatment target for several diseases. However, the function of PDI in the peripheral sensory nervous system is unclear. Here we report the expression and secretion of PDI from primary sensory neurons is upregulated in inflammatory and neuropathic pain models. Deletion of PDI in nociceptive DRG neurons results in a reduction in inflammatory and neuropathic heat hyperalgesia. We demonstrate that secreted PDI activates TRPV1 channels through oxidative modification of extracellular cysteines of the channel, indicating that PDI acts as an unconventional positive modulator of TRPV1. These findings suggest that PDI in primary sensory neurons plays an important role in development of heat hyperalgesia and can be a potential therapeutic target for chronic pain. [Display omitted] •Nociceptive DRG neurons secret PDI, which is enhanced during chronic pain•PDI serves as an endogenous TRPV1 activator•PDI activates TRPV1 through oxidation of extracellular cysteines of TRPV1•PDI is a potential therapeutic target for chronic pain Zhang et al. show upregulation of expression and secretion of PDI in dorsal root ganglion neurons in chronic pain conditions. Secreted PDI acts as endogenous TRPV1 activator by catalytic oxidation of extracellular cysteines of the channel, which is relevant to the development of heat hyperalgesia in chronic pain.