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

The conversion of force sensation into electrical signals via mechano-electrical transduction (MET) is considered the key step in auditory perception. Here, we find that the G-protein-coupled receptor (GPCR) LPHN2/ADGRL2 is expressed at the tips of stereocilia in cochlear hair cells and is associated with MET channel components. Hair-cell-specific LPHN2 deficiency causes hearing loss and impaired MET responses. A specific inhibitor of LPHN2 also reversibly blocks the MET response. Mechanistically, the administration of force to LPHN2 activates TMC1 through physical interaction and causes conformational changes in TMC1. Furthermore, the sensing of force by LPHN2 stimulates the Ca²⁺response and neurotransmitter release in hair cells. Finally, expression of LPHN2-GAIN in cochlear hair cells of Lphn2-deficient mice prevents hearing loss. Our work provides evidence that the GPCR can play modulatory roles in the auditory process through a TMC1-coupled mechanism.