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
Shanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Fudan University, Shanghai, China.
School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Cell Discov. 2024 Jun 18;10(1):66. doi: 10.1038/s41421-024-00678-9.
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 Ser to Pro. 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 Ca 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.
热感觉对于所有生物体的生存、繁殖和适应至关重要，但其机制尚未完全被理解。在这里，我们发现TMC6，一种功能未知的膜蛋白，在背根神经节（DRG）神经元中高度表达，并作为一种与Gαq偶联的G蛋白偶联受体（GPCR）样受体来感知有害热。TMC6基因敲除小鼠在有害热感觉方面表现出严重受损，而对冷、温、触觉和机械性疼痛的感知保持正常。进一步的研究表明，TMC6通过其跨越丝氨酸至脯氨酸的细胞内C末端区域与Gαq相互作用。在DRG神经元中使用多肽特异性破坏这种相互作用、基因敲除Gαq或药理学阻断Gαq偶联的GPCR信号传导，可以复制TMC6基因敲除小鼠在有害热感觉方面的表型。有害热刺激触发TMC6转染而非对照载体转染的HEK293T细胞内质网（ER）的细胞内钙释放，这可以通过阻断PLC或IP3R而显著抑制。同样，在敲除TMC6或阻断Gαq/PLC/IP3R信号通路时，有害热诱导的ER细胞内钙释放和DRG神经元的动作电位也大大降低。总之，我们的研究结果表明，TMC6可以直接作为一种与Gαq偶联的GPCR样受体来感知有害热。
