The force-sensing GPCR LPHN2 is indispensable for normal auditory function

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.