Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse
Isabelle Roux, Saaid Safieddine, Régis Nouvian, M'hamed Grati, Marie-Christine Simmler, Amel Bahloul, Isabelle Perfettini, Morgane Le Gall, Philippe Rostaing, Ghislaine Hamard, Antoine Triller, Paul Avan, Tobias Moser, Christine Petit, Isabelle Roux, Saaid Safieddine, Régis Nouvian, M'hamed Grati, Marie-Christine Simmler, Amel Bahloul, Isabelle Perfettini, Morgane Le Gall, Philippe Rostaing, Ghislaine Hamard, Antoine Triller, Paul Avan, Tobias Moser, Christine Petit
Abstract
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.
Source: PubMed