Protein disulfide isomerase modulation of TRPV1 controls heat hyperalgesia in chronic pain
Yongxue Zhang,
Qi Miao,
Sai Shi,
Han Hao,
Xinmeng Li,
Zeyao Pu,
Yakun Yang,
Hailong An,
Wei Zhang,
Youzhen Kong,
Xu Pang,
Cunyang Gu,
Nikita Gamper,
Yi Wu,
Hailin Zhang,
Xiaona Du
Affiliations
Yongxue Zhang
Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei, China; Department of Pharmacy, The First Hospital of Handan, Handan, Hebei, China
Qi Miao
Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei, China
Sai Shi
Key Laboratory of Molecular Biophysics, Institute of Biophysics, School of Science, Hebei University of Technology, Tianjin, Hebei, China
Han Hao
Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei, China
Xinmeng Li
Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei, China
Zeyao Pu
Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei, China
Yakun Yang
Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei, China
Hailong An
Key Laboratory of Molecular Biophysics, Institute of Biophysics, School of Science, Hebei University of Technology, Tianjin, Hebei, China
Wei Zhang
Department of Spinal Surgery of the Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
Youzhen Kong
Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei, China
Xu Pang
Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei, China
Cunyang Gu
Department of Pathology, The Fourth Hospital of Shijiazhuang, Shijiazhuang, Hebei, China
Nikita Gamper
Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei, China; Faculty of Biological Sciences, University of Leeds, LS2 9JT Leeds, UK
Yi Wu
National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital, Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, Suzhou 215123, China; Corresponding author
Hailin Zhang
Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei, China; Corresponding author
Xiaona Du
Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei, China; Corresponding author
Summary: 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.