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

作者：Yongxue Zhang, Qi Miao, Sai Shi, Han Hao, Xinmeng Li, Zeyao Pu, Yakun Yang, Hailong An, Wei Zhang, Youzhen Kong, Pang Xu, Cunyang Gu, Nikita Gamper, Yi Wu, Hailin Zhang, Xiaona Du · 发表于：Cell Reports · 年份：2022 · DOI：10.1016/j.celrep.2022.110625 · 被引用次数：15 · 研究领域：Ion Channels and Receptors、Pain Mechanisms and Treatments、Exercise and Physiological Responses

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.