Force sensation by a Gs-coupled adhesion GPCR mediates equilibrioception by increasing vestibular hair cell membrane excitability and CNGA3 coupling

yang, z.; zhou, s.; zhang, q.; liu, w.; sun, y.; qi, j.; guan, y.; wang, m.; song, z.; yang, w.; Yu, X.; chai, r.; Sun, J.

doi:10.1101/2023.10.24.563886

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bioRxiv · 10.1101/2023.10.24.563886

Force sensation by a Gs-coupled adhesion GPCR mediates equilibrioception by increasing vestibular hair cell membrane excitability and CNGA3 coupling

yang, z.·zhou, s.·zhang, q.·liu, w.·sun, y.·qi, j.·guan, y.·wang, m.·song, z.·yang, w.·Yu, X.·chai, r.·Sun, J.

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Abstract

AbstractEquilibrioception is essential for the perception and navigation of mammals in the three-dimensional world. A rapid mechanoelectrical transduction (MET) response in vestibular hair cells plays a critical role in positional and motional perception. Here, we identified that the G protein-coupled receptor LPHN2/ADGRL2, which is expressed in the apical membrane of utricular hair cells, is required for maintenance of normal balance. Hair cell-specific Lphn2 deficiency in mice impaired both balance behaviors and MET responses. Functional analyses using Pou4f3-CreER+/-; Lphn2fl/fl mice and LPHN2-specific inhibitors revealed that LPHN2 regulated the tip link-independent MET current at the apical surface of the utricular hair cell by converting force stimuli into transmembrane channel-like protein 1 (TMC1) activity. Force sensation by LPHN2 also induced glutamate release and calcium signaling in utricular hair cells. Reintroduction of LPHN2 into the hair cells of Lphn2-deficient mice restored the vestibular functions and MET responses. Our data suggest an indispensable role for a mechanosensitive GPCR in equilibrioception.

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yang, z., zhou, s., zhang, q., liu, w., sun, y., qi, j., guan, y., wang, m., song, z., yang, w., Yu, X., chai, r., Sun, J.. 2023-10-27. Force sensation by a Gs-coupled adhesion GPCR mediates equilibrioception by increasing vestibular hair cell membrane excitability and CNGA3 coupling. https://doi.org/10.1101/2023.10.24.563886

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