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

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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 Ca2+ and displays Ca2+-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 Ca2+ current. Thus, otoferlin is essential for a late step of synaptic vesicle exocytosis and may act as the major Ca2+ sensor triggering membrane fusion at the IHC ribbon synapse.

Original languageEnglish (US)
Pages (from-to)277-289
Number of pages13
JournalCell
Volume127
Issue number2
DOIs
StatePublished - Oct 20 2006

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Roux, I., Safieddine, S., Nouvian, R., Grati, M., Simmler, M. C., Bahloul, A., Perfettini, I., Le Gall, M., Rostaing, P., Hamard, G., Triller, A., Avan, P., Moser, T., & Petit, C. (2006). Otoferlin, Defective in a Human Deafness Form, Is Essential for Exocytosis at the Auditory Ribbon Synapse. Cell, 127(2), 277-289. https://doi.org/10.1016/j.cell.2006.08.040