Copine-6 is a TRPM3 escort protein controlling the sensitivity of sensory neurons to noxious heat

  • EMBO J. 2025 Jun 19. doi: 10.1038/s44318-025-00487-0.
Yiting Gao  #  1 ,  Shengxiang Yan  #  1 ,  Zhongyang Zhang  1 ,  Jieyao Zhang  1 ,  Meng Yang  1 ,  Shihab Shah  2 ,  Sofia Figoli  2 ,  Qi Jing  3 ,  Haixia Gao  4 ,  Nikita Gamper  5  6
Affiliations
  • 1. Department of Pharmacology; The Key Laboratory of New Drug Pharmacology and Toxicology; The Key Laboratory of Neural and Vascular Biology, Ministry of Education; The Hebei Collaboration and Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Diseases, Hebei Medical University, Shijiazhuang, Hebei, China.
  • 2. School of Biomedical Sciences; Faculty of Biological Sciences, University of Leeds, Leeds, UK.
  • 3. Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4. Department of Pharmacology; The Key Laboratory of New Drug Pharmacology and Toxicology; The Key Laboratory of Neural and Vascular Biology, Ministry of Education; The Hebei Collaboration and Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Diseases, Hebei Medical University, Shijiazhuang, Hebei, China. [email protected].
  • 5. Department of Pharmacology; The Key Laboratory of New Drug Pharmacology and Toxicology; The Key Laboratory of Neural and Vascular Biology, Ministry of Education; The Hebei Collaboration and Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Diseases, Hebei Medical University, Shijiazhuang, Hebei, China. [email protected].
  • 6. School of Biomedical Sciences; Faculty of Biological Sciences, University of Leeds, Leeds, UK. [email protected].
  • # Contributed equally.
PMID: 40537608 DOI: 10.1038/s44318-025-00487-0
Abstract

Copine-6 is a calcium-sensitive phospholipid-binding protein of the evolutionarily conserved Copine family. In the central nervous system, Copine-6 regulates function of some neurotransmitter receptors and structural plasticity of dendritic spines, influencing learning and memory. Copine-6 is expressed in peripheral somatosensory neurons, but its role in somatosensation remains unclear. Here we demonstrate that Copine-6 plays a prominent role in thermosensation. Copine-6 is highly expressed in a subpopulation of dorsal root ganglia (DRG) neurons that also express thermosensitive TRPM3 channels. Genetic deletion or downregulation of Copine-6 in the DRG in vivo selectively impairs sensitivity to noxious heat, without affecting Other sensory modalities, and significantly reduced TRPM3 currents in DRG neurons. Copine-6 interacts with TRPM3 via its von Willebrand factor A (vWA) domain, promoting TRPM3 translocation to the plasma membrane. Thus, Copine-6-dependent TRPM3 trafficking determines noxious-heat sensitivity range of the nerve fibers; moreover, Copine-6 is an accessible target for the treatment of heat hypersensitivity in chronic inflammatory and neuropathic pain.

Keywords
Copine-6; Dorsal Root Ganglion; Pain; Thermosensation; Transient Receptor Potential Melastatin-3 (TRPM3).
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