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

Abstract

AbstractEquilibrioception is essential for the perception and navigation of mammals in the three-dimensional world. The mechanoelectrical transduction (MET) process in vestibular hair cells is believed to play central roles in positional and motional sensation. However, the direct equilibrioception sensor at the molecular level is not clear, and the mechanism underlying the MET process in vestibular hair cells remains elusive. Here, we identified that the G protein-coupled receptor LPHN2, which is expressed in the cuticular plate of utricular hair cells, is required for normal balance maintenance. The sensation of force by LPHN2 in the utricular hair cells increased intracellular cAMP levels in a Gs-dependent manner. The direct association of LPHN2 with the ion channel CNGA3 and increased cAMP levels enabled the activation of CNGA3, which induced calcium influx and membrane depolarization. These cellular signals and balance-related functions were significantly weakened inLphn2+/-mice,Pou4f3-CreER+/-Lphn2fl/flmice andPou4f3-CreER+/-Cnga3fl/+mice and could be suppressed by Gs or CNGA3 inhibitors. Collectively, our data suggested that LPHN2 could be a direct equilibrioception sensor in utricular hair cells by converting the force sensation to electrical signals through Gs and CNGA3 coupling. Both GPCR members and the ion channel CNGA3 could be essential elements for equilibrioception.