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

doi:10.1016/j.celrep.2022.110625

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

Cell Rep. 2022 Apr 5;39(1):110625. doi: 10.1016/j.celrep.2022.110625.

Authors

Yongxue Zhang¹, Qi Miao², Sai Shi³, Han Hao², Xinmeng Li², Zeyao Pu², Yakun Yang², Hailong An³, Wei Zhang⁴, Youzhen Kong², Xu Pang², Cunyang Gu⁵, Nikita Gamper⁶, Yi Wu⁷, Hailin Zhang⁸, Xiaona Du⁹

Affiliations

¹ 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.
² 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.
³ Key Laboratory of Molecular Biophysics, Institute of Biophysics, School of Science, Hebei University of Technology, Tianjin, Hebei, China.
⁴ Department of Spinal Surgery of the Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
⁵ Department of Pathology, The Fourth Hospital of Shijiazhuang, Shijiazhuang, Hebei, China.
⁶ 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.
⁷ 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. Electronic address: wuy@suda.edu.cn.
⁸ 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. Electronic address: zhanghl@hebmu.edu.cn.
⁹ 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. Electronic address: duxiaona@hebmu.edu.cn.

PMID: 35385753
DOI: 10.1016/j.celrep.2022.110625

Abstract

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.

Keywords: CP: Neuroscience; DRG; PDI; TRPV1; chronic pain; cysteine oxidation.

MeSH terms

Animals
Chronic Pain*
Hot Temperature
Humans
Hyperalgesia / metabolism
Mice
Oxidation-Reduction
Protein Disulfide-Isomerases* / metabolism
Protein Folding
TRPV Cation Channels / genetics
TRPV Cation Channels / metabolism

Substances

TRPV Cation Channels
TRPV1 protein, human
Protein Disulfide-Isomerases

Grants and funding

212302/Z/18/Z/WT_/Wellcome Trust/United Kingdom