Abstract
The conversion of force sensation into electrical signals via mechanoelectrical transduction (MET) is considered the key step in auditory perception. Here, we found that G protein-coupled receptor (GPCR) LPHN2/ADGRL2 was expressed at the tips of stereocilia in cochlear hair cells and was associated with MET channel components. Hair cell-specific LPHN2 deficiency caused hearing loss and impaired MET responses. A specific inhibitor of LPHN2, developed by in silico screening and pharmacological characterization, reversibly blocked the MET response. Mechanistically, administration of force to LPHN2 activated TMC1 through direct interaction and caused conformational changes in TMC1 in vitro. Furthermore, the sensing of force by LPHN2 stimulated Ca2+ responses and neurotransmitter release in hair cells. Finally, hearing loss in LPHN2-deficient mice was reversed by the re-expression of LPHN2-GAIN in cochlear hair cells. The important roles of LPHN2 in auditory perception and a TMC-coupled force sensor indicated that GPCRs could be candidate auditory receptors.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
All figure updated Author list updated 1. Fluid-jet assay was employed to record the MET currents, which revealed an indispensable role of LPHN2 in normal MET response in cochlear hair cells. 2. A reversible and selective chemical inhibitor of LPHN2 was developed through structure-based virtual screening, which verified the indispensable role of LPHN2 in MET response. 3. Biophysical studies were performed to support that the sensation of force by LPHN2 could induce conformational changes in TMC1, leading to the opening of its ion-conduction pore. 4. The author list has been changed according to their respective contributions to the revised version of the manuscript.
Data availability
All data are available upon reasonable request from the corresponding authors.
