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Volume 35, No 4, Apr 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 4, April 2025: 243-264   |  Open Access

ORIGINAL ARTICLES

A force-sensitive adhesion GPCR is required for equilibrioception

Zhao Yang1,† , Shu-Hua Zhou1,2,3,† , Qi-Yue Zhang1,† , Zhi-Chen Song1,3,† , Wen-Wen Liu4,† , Yu Sun5,† , Ming-Wei Wang6,7,† , Xiao-Long Fu8 , Kong-Kai Zhu6 , Ying Guan7 , Jie-Yu Qi2 , Xiao-Hui Wang5 , Yu-Nan Sun9 , Yan Lu1 , Yu-Qi Ping8 , Yue-Tong Xi1 , Zhen-Xiao Teng8 , Lei Xu4 , Peng Xiao1,6 , Zhi-Gang Xu10 , Wei Xiong11 , Wei Qin12 , Wei Yang13,* , Fan Yi14,* , Ren-Jie Chai2,* , Xiao Yu3,* , Jin-Peng Sun1,6,9

1NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, and New Cornerstone Science Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
2State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health Jiangsu Province HighTech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu, China
3Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
4Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
5Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
6Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
7Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
8Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
9State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
10Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, Shandong University School of Life Sciences, Qingdao, Shandong, China
11Chinese Institute for Brain Research, Beijing, China
12School of Physics, State Key Laboratory of Crystal Materials, Shandong University, Jinan, Shandong, China
13Department of Biophysics, and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
14Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
These authors contributed equally: Zhao Yang, Shu-Hua Zhou, Qi-Yue Zhang, Zhi-Chen Song, Wen-Wen Liu, Yu Sun, Ming-Wei Wang
Correspondence: Wei Yang(yangwei@zju.edu.cn)Fan Yi(fanyi@sdu.edu.cn)Ren-Jie Chai(renjiec@seu.edu.cn)Xiao Yu(yuxiao@sdu.edu.cn)

Equilibrioception (sensing of balance) is essential for mammals to perceive and navigate the three-dimensional world. A rapid mechanoelectrical transduction (MET) response in vestibular hair cells is crucial for detecting position and motion. Here, we identify the G protein-coupled receptor (GPCR) LPHN2/ADGRL2, expressed on the apical membrane of utricular hair cells, as essential for maintaining normal balance. Loss of LPHN2 specifically in hair cells impaired both balance behavior and the MET response in mice. Functional analyses using hair-cell-specific Lphn2-knockout mice and an LPHN2-specific inhibitor suggest that LPHN2 regulates tip-link-independent MET currents at the apical surface of utricular hair cells. Mechanistic studies in a heterologous system show that LPHN2 converts force stimuli into increased open probability of transmembrane channel-like protein 1 (TMC1). LPHN2-mediated force sensation triggers glutamate release and calcium signaling in utricular hair cells. Importantly, reintroducing LPHN2 into the hair cells of Lphn2-deficient mice restores vestibular function and MET response. Our data reveal that a mechanosensitive GPCR is required for equilibrioception.


https://doi.org/10.1038/s41422-025-01075-x

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