A force-sensitive adhesion GPCR is required for equilibrioception
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.
Authors
- Zhigang Xu (ORCID: https://orcid.org/0000-0003-0082-7297)
- Wei Yang (ORCID: https://orcid.org/0000-0003-3065-1843)
- Jieyu Qi (ORCID: https://orcid.org/0000-0001-8780-0710)
- Zhao Yang (ORCID: https://orcid.org/0000-0001-6948-1912)
- Fan Yi (ORCID: https://orcid.org/0000-0001-8634-9788)
- Xiaolong Fu (ORCID: https://orcid.org/0000-0002-3884-0916)
- Kongkai Zhu (ORCID: https://orcid.org/0000-0001-8879-3276)
- Yu Sun (ORCID: https://orcid.org/0000-0002-1771-3715)
- Yan Lu (ORCID: https://orcid.org/0000-0002-8894-1969)
- Ming-Wei Wang
- Xiao Yu (ORCID: https://orcid.org/0000-0003-1119-8334)
- Ying Guan (ORCID: https://orcid.org/0000-0003-2781-4285)
- Renjie Chai (ORCID: https://orcid.org/0000-0002-3885-543X)
- Wei Xiong (ORCID: https://orcid.org/0000-0002-2784-7696)
- Yue-Tong Xi
- Wei Qin (ORCID: https://orcid.org/0000-0003-2161-387X)
- Zhen-Xiao Teng
- Wenwen Liu (ORCID: https://orcid.org/0000-0001-8877-6601)
- Jin‐Peng Sun (ORCID: https://orcid.org/0000-0003-3572-1580)
- Peng Xiao (ORCID: https://orcid.org/0000-0002-9809-3481)
- Yunan Sun (ORCID: https://orcid.org/0009-0000-1579-1253)
- Song Zhichen
- Lei Xu (ORCID: https://orcid.org/0000-0002-5696-2968)
- Yu-Qi Ping (ORCID: https://orcid.org/0000-0002-9707-7156)
- Shuhua Zhou (ORCID: https://orcid.org/0000-0001-5599-8400)
- Xiaohui Wang (ORCID: https://orcid.org/0009-0006-5575-8603)
- Qiyue Zhang (ORCID: https://orcid.org/0000-0003-1599-4477)
Institutions
- Union Hospital (HK)
- Shandong University (CN)
- Peking University (CN)
- Second Hospital of Shandong University (CN)
- Zhongda Hospital Southeast University (CN)
- Chinese Institute for Brain Research (CN)
- Qilu Hospital of Shandong University (CN)
- Shandong First Medical University (CN)
- Huazhong University of Science and Technology (CN)
- Zhejiang University (CN)
- Southeast University (CN)
Publication Details
- Journal
- Cell Research
- Published
- 2025-02-18
- DOI
- https://doi.org/10.1038/s41422-025-01075-x
- Citations
- 21
- Primary Topic
- Hearing, Cochlea, Tinnitus, Genetics
- Type
- article
- Field-Weighted Citation Impact
- 30.76
Funders
- Tencent
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Peking University
- Foundation for Innovative Research Groups of the National Natural Science Foundation of China
- National Outstanding Youth Science Fund Project of National Natural Science Foundation of China