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

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.