A force-sensitive adhesion GPCR is required for equilibrioception

Zhao Yang; Shu Hua Zhou; Qi Yue Zhang; Zhi Chen Song; Wen Wen Liu; Yu Sun; Ming Wei Wang; Xiao Long Fu; Kong Kai Zhu; Ying Guan; Jie Yu Qi; Xiao Hui Wang; Yu Nan Sun; Yan Lu; Yu Qi Ping; Yue Tong Xi; Zhen Xiao Teng; Lei Xu; Peng Xiao; Zhi Gang Xu; Wei Xiong; Wei Qin; Wei Yang; Fan Yi; Ren Jie Chai; Xiao Yu; Jin Peng Sun

doi:10.1038/s41422-025-01075-x

A force-sensitive adhesion GPCR is required for equilibrioception

Zhao Yang
, Shu Hua Zhou
, Qi Yue Zhang
, Zhi Chen Song
, Wen Wen Liu
, Yu Sun
, Ming Wei Wang
, Xiao Long Fu
, Kong Kai Zhu
, Ying Guan
, Jie Yu Qi
, Xiao Hui Wang
, Yu Nan Sun
, Yan Lu
, Yu Qi Ping
, Yue Tong Xi
, Zhen Xiao Teng
, Lei Xu
, Peng Xiao
, Zhi Gang Xu

Wei Xiong, Wei Qin, Wei Yang^*, Fan Yi^*, Ren Jie Chai^*, Xiao Yu^*, Jin Peng Sun^*

^*此作品的通讯作者

Qilu Hospital of Shandong University
Southeast University, Nanjing
Cheeloo College of Medicine, Shandong University
Huazhong University of Science and Technology
Shandong First Medical University & Shandong Academy of Medical Sciences
Peking University
Shandong University
Chinese Institute for Brain Research
Zhejiang University

科研成果: 期刊稿件 › 文章 › 同行评审

18 引用（Scopus）

摘要

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.

源语言	英语
文章编号	e16041
页（从-至）	243-264
页数	22
期刊	Cell Research
卷	35
期	4
DOI	https://doi.org/10.1038/s41422-025-01075-x
出版状态	已出版 - 4月 2025
已对外发布	是

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Yang, Z., Zhou, S. H., Zhang, Q. Y., Song, Z. C., Liu, W. W., Sun, Y., Wang, M. W., Fu, X. L., Zhu, K. K., Guan, Y., Qi, J. Y., Wang, X. H., Sun, Y. N., Lu, Y., Ping, Y. Q., Xi, Y. T., Teng, Z. X., Xu, L., Xiao, P., ... Sun, J. P. (2025). A force-sensitive adhesion GPCR is required for equilibrioception. Cell Research, 35(4), 243-264. 文章 e16041. https://doi.org/10.1038/s41422-025-01075-x

@article{76ba6e86081544149710571a1b734db9,

title = "A force-sensitive adhesion GPCR is required for equilibrioception",

abstract = "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.",

author = "Zhao Yang and Zhou, \{Shu Hua\} and Zhang, \{Qi Yue\} and Song, \{Zhi Chen\} and Liu, \{Wen Wen\} and Yu Sun and Wang, \{Ming Wei\} and Fu, \{Xiao Long\} and Zhu, \{Kong Kai\} and Ying Guan and Qi, \{Jie Yu\} and Wang, \{Xiao Hui\} and Sun, \{Yu Nan\} and Yan Lu and Ping, \{Yu Qi\} and Xi, \{Yue Tong\} and Teng, \{Zhen Xiao\} and Lei Xu and Peng Xiao and Xu, \{Zhi Gang\} and Wei Xiong and Wei Qin and Wei Yang and Fan Yi and Chai, \{Ren Jie\} and Xiao Yu and Sun, \{Jin Peng\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = apr,

doi = "10.1038/s41422-025-01075-x",

language = "English",

volume = "35",

pages = "243--264",

journal = "Cell Research",

issn = "1001-0602",

publisher = "Springer Nature",

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Yang, Z, Zhou, SH, Zhang, QY, Song, ZC, Liu, WW, Sun, Y, Wang, MW, Fu, XL, Zhu, KK, Guan, Y, Qi, JY, Wang, XH, Sun, YN, Lu, Y, Ping, YQ, Xi, YT, Teng, ZX, Xu, L, Xiao, P, Xu, ZG, Xiong, W, Qin, W, Yang, W, Yi, F, Chai, RJ, Yu, X & Sun, JP 2025, 'A force-sensitive adhesion GPCR is required for equilibrioception', Cell Research, 卷 35, 号码 4, e16041, 页码 243-264. https://doi.org/10.1038/s41422-025-01075-x

TY - JOUR

T1 - A force-sensitive adhesion GPCR is required for equilibrioception

AU - Yang, Zhao

AU - Zhou, Shu Hua

AU - Zhang, Qi Yue

AU - Song, Zhi Chen

AU - Liu, Wen Wen

AU - Sun, Yu

AU - Wang, Ming Wei

AU - Fu, Xiao Long

AU - Zhu, Kong Kai

AU - Guan, Ying

AU - Qi, Jie Yu

AU - Wang, Xiao Hui

AU - Sun, Yu Nan

AU - Lu, Yan

AU - Ping, Yu Qi

AU - Xi, Yue Tong

AU - Teng, Zhen Xiao

AU - Xu, Lei

AU - Xiao, Peng

AU - Xu, Zhi Gang

AU - Xiong, Wei

AU - Qin, Wei

AU - Yang, Wei

AU - Yi, Fan

AU - Chai, Ren Jie

AU - Yu, Xiao

AU - Sun, Jin Peng

PY - 2025/4

Y1 - 2025/4

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85218166367

U2 - 10.1038/s41422-025-01075-x

DO - 10.1038/s41422-025-01075-x

M3 - Article

C2 - 39966628

AN - SCOPUS:85218166367

SN - 1001-0602

VL - 35

SP - 243

EP - 264

JO - Cell Research

JF - Cell Research

IS - 4

M1 - e16041

ER -

A force-sensitive adhesion GPCR is required for equilibrioception

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