胞囊
基诺西林
前庭系统
细胞生物学
毛细胞
离子通道
细胞内
第二信使系统
内耳
G蛋白偶联受体
联轴节(管道)
受体
神经科学
化学
生物物理学
生物
信号转导
生物化学
材料科学
冶金
作者
Yang Zhao,Shuhua Zhou,Ming-Wei Wang,Ping Yu,Xiaoli Fu,Ru-Jia Zhao,peng xiao,Y. Lu,Q. Zhang,Z. M. Song,Yue-Tong Xi,Hui Lin,Yuan Zheng,Wei Qin,Fan Yi,Xiao Yu,Renjie Chai,Jing Sun
标识
DOI:10.1101/2023.10.24.563882
摘要
Abstract The maintenance of normal balance sensing is a fundamental prerequisite for virtually every activity of daily life. As one set most important balance information collectors, vestibular hair cells convert mechanical stimuli from head movement into electrical signals through a mechanoelectrical transduction (MET) process. The molecular mechanism underlying equilibrioception and MET in vestibular hair cells is not well understood but is generally believed to be mediated by ion channels. However, whether these procedures are also mediated by other receptors, such as GPCRs, which are known to govern light, odorant and taste sensing, is not known. Here, by screening the expression of force-sensitive adhesion GPCRs in vestibular hair cells and phenotype profiling in animal models, we identified that a seven-transmembrane receptor, GPR133, was able to sense force in utricle hair cells and was required for maintenance of normal equilibrioception. Notably, GPR133 converted mechanical stimuli into changes in intracellular cAMP levels through Gi engagement and then modulated plasma membrane excitability and mediated MET by coupling to CNGA3 activity changes in approximately 30% of GPR133-expressing utricle hair cells. GPR133-mediated MET and its coupling with CNGA3 were recapitulated by an in vitro reconstitution system. Further chemical labeling, mass spectrometry and cryo-EM analysis provided potential structural information on force-induced GPR133 activation and Gi3 engagement. Collectively, our findings reveal the essential role of GPR133 in the maintenance of normal equilibrioception and suggest that GPCR family members can participate in the MET process in utricle hair cells through modulation of intracellular second messenger levels and ion channel coupling.
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