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

Cell Reports (Apr 2022)

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

Journal volume & issue: Vol. 39, no. 1
p. 110625

Abstract

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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.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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