TMC6 作为一种类似 GPCR 的受体,通过 Gαq 信号传导来感知有害热量。

IF 13 1区 生物学 Q1 CELL BIOLOGY
Chen Zhang, Fang Tong, Bin Zhou, Mingdong He, Shuai Liu, Xiaomeng Zhou, Qiang Ma, Tianyu Feng, Wan-Jie Du, Huan Yang, Hao Xu, Lei Xiao, Zhen-Zhong Xu, Cheng Zhu, Ruiqi Wu, Yan-Qing Wang, Qingjian Han
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引用次数: 0

摘要

热感觉对所有生物的生存、传播和适应至关重要,但其机制尚未完全清楚。在这里,我们发现 TMC6 是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,并作为一种类似 Gαq 的 G 蛋白偶联受体(GPCR)来感知有害热。缺失 TMC6 的小鼠在对冷、暖、触觉和机械痛的感知保持正常的同时,对有害热的感觉却表现出严重的障碍。进一步的研究表明,TMC6 通过跨越 Ser780 至 Pro810 的胞内 C 端区域与 Gαq 相互作用。在DRG神经元中使用多肽、基因消融Gαq或药物阻断Gαq耦合GPCR信号传导来具体破坏这种相互作用,可以复制TMC6缺失小鼠在痛热感觉方面的表型。毒性热刺激会触发细胞内钙从TMC6转染的HEK293T细胞内质网(ER)释放,而不是对照载体转染的HEK293T细胞。同样,当消融 TMC6 或阻断 Gαq/PLC/IP3R 信号通路时,有害热诱导的细胞内 Ca2+ 从 ER 的释放和 DRG 神经元的动作电位也会大大降低。总之,我们的研究结果表明,TMC6 可直接作为 Gαq 偶联的 GPCR 样受体感知有害热。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

TMC6 functions as a GPCR-like receptor to sense noxious heat via Gαq signaling.

TMC6 functions as a GPCR-like receptor to sense noxious heat via Gαq signaling.

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.

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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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