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<p>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 <i>Lphn2</i>-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 <i>Lphn2</i>-deficient mice restores vestibular function and MET response. Our data reveal that a mechanosensitive GPCR is required for equilibrioception.</p>

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A force-sensitive adhesion GPCR is required for equilibrioception

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月18日

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  • 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

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.