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- Title
TMC6 functions as a GPCR-like receptor to sense noxious heat via Gαq signaling.
- Authors
Zhang, Chen; Tong, Fang; Zhou, Bin; He, Mingdong; Liu, Shuai; Zhou, Xiaomeng; Ma, Qiang; Feng, Tianyu; Du, Wan-Jie; Yang, Huan; Xu, Hao; Xiao, Lei; Xu, Zhen-Zhong; Zhu, Cheng; Wu, Ruiqi; Wang, Yan-Qing; Han, Qingjian
- Abstract
Thermosensation is vital for the survival, propagation, and adaption of all organisms, but its mechanism is not fully understood yet. Here, we find that TMC6, a membrane protein of unknown function, is highly expressed in dorsal root ganglion (DRG) neurons and functions as a Gαq-coupled G protein-coupled receptor (GPCR)-like receptor to sense noxious heat. TMC6-deficient mice display a substantial impairment in noxious heat sensation while maintaining normal perception of cold, warmth, touch, and mechanical pain. Further studies show that TMC6 interacts with Gαq via its intracellular C-terminal region spanning Ser780 to Pro810. Specifically disrupting such interaction using polypeptide in DRG neurons, genetically ablating Gαq, or pharmacologically blocking Gαq-coupled GPCR signaling can replicate the phenotype of TMC6 deficient mice regarding noxious heat sensation. Noxious heat stimulation triggers intracellular calcium release from the endoplasmic reticulum (ER) of TMC6- but not control vector-transfected HEK293T cell, which can be significantly inhibited by blocking PLC or IP3R. Consistently, noxious heat-induced intracellular Ca2+ release from ER and action potentials of DRG neurons largely reduced when ablating TMC6 or blocking Gαq/PLC/IP3R signaling pathway as well. In summary, our findings indicate that TMC6 can directly function as a Gαq-coupled GPCR-like receptor sensing noxious heat.
- Subjects
DORSAL root ganglia; ACTION potentials; CALCIUM channels; INTRACELLULAR calcium; MEMBRANE proteins; ENDOPLASMIC reticulum; HEAT shock proteins
- Publication
Cell Discovery, 2024, Vol 10, Issue 1, p1
- ISSN
2056-5968
- Publication type
Article
- DOI
10.1038/s41421-024-00678-9