Force-sensing LPHN2 is indispensable for normal hearing and mediates MET in cochleae through Gs and CNGA3 coupling

Abstract

AbstractAuditory perception enables acoustic experiences, including listening to melodious music and engaging in linguistic communication. Conversion of the force sensation into electrical signals via mechanoelectrical transduction (MET) in cochlear hair cells is the key step for auditory perception; however, the sound receptor for auditory perception at the molecular level is not clear. Here, we found that hair cell-specific deficiency of the G protein-coupled receptor LPHN2 inPou4f3-CreER+/−Lphn2fl/flmice or pharmacological blockade of CNG ion channels in mice severely impaired hearing. Importantly, sensation of force by LPHN2 not only increased intracellular cAMP and calcium levels but also elicited rapid membrane depolarization of cochlear hair cells via Gs-dependent CNGA3 coupling. Both LPHN2 and CNGA3 were expressed at the stereocilia and cuticular plates and associated with each other. Notably, hearing loss in LPHN2-deficient mice was almost fully reversed by re-expression of LPHN2-GAIN in cochlear hair cells. Therefore, we propose that LPHN2 acts as a direct sound sensor in cochlear hair cells by mediating MET through Gs and CNGA3 coupling. Furthermore, both GPCR members and ion channels modulated by second messengers might actively participate in the MET process during auditory perception.