Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse.

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Roux, Isabelle | Safieddine, Saaid | Nouvian, Régis | Grati, M'Hamed | Simmler, Marie-Christine | Bahloul, Amel | Perfettini, Isabelle | Le Gall, Morgane | Rostaing, Phillipe | Hamard, Ghislaine | Triller, Antoine | Avan, Paul | Moser, Tobias | Petit, Christine

Edité par CCSD ; Elsevier -

International audience. The auditory inner hair cell (IHC) ribbon synapse operates with an exceptional temporal precision and maintains a high level of neurotransmitter release. However, the molecular mechanisms underlying IHC synaptic exocytosis are largely unknown. We studied otoferlin, a predicted C2-domain transmembrane protein, which is defective in a recessive form of human deafness. We show that otoferlin expression in the hair cells correlates with afferent synaptogenesis and find that otoferlin localizes to ribbon-associated synaptic vesicles. Otoferlin binds Ca(2+) and displays Ca(2+)-dependent interactions with the SNARE proteins syntaxin1 and SNAP25. Otoferlin deficient mice (Otof(-/-)) are profoundly deaf. Exocytosis in Otof(-/-) IHCs is almost completely abolished, despite normal ribbon synapse morphogenesis and Ca(2+) current. Thus, otoferlin is essential for a late step of synaptic vesicle exocytosis and may act as the major Ca(2+) sensor triggering membrane fusion at the IHC ribbon synapse.

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