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 Yang^1,† , Shu-Hua Zhou^1,2,3,† , Qi-Yue Zhang^1,† , Zhi-Chen Song^1,3,† , Wen-Wen Liu^4,† , Yu Sun^5,† , Ming-Wei Wang^6,7,† , 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 Xiao^1,6 , Zhi-Gang Xu¹⁰ , Wei Xiong¹¹ , Wei Qin¹² , Wei Yang^13,* , Fan Yi^14,* , Ren-Jie Chai^2,* , Xiao Yu^3,* , Jin-Peng Sun^1,6,9

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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