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

doi:10.1016/j.cell.2006.08.040

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

Otolaryngology

Research output: Contribution to journal › Article

348 Scopus citations

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 language	English (US)
Pages (from-to)	277-289
Number of pages	13
Journal	Cell
Volume	127
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2006.08.040
State	Published - 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

Otoferlin, Defective in a Human Deafness Form, Is Essential for Exocytosis at the Auditory Ribbon Synapse. / Roux, Isabelle; Safieddine, Saaid; Nouvian, Régis; Grati, M'hamed; Simmler, Marie Christine; Bahloul, Amel; Perfettini, Isabelle; Le Gall, Morgane; Rostaing, Philippe; Hamard, Ghislaine; Triller, Antoine; Avan, Paul; Moser, Tobias; Petit, Christine.

In: Cell, Vol. 127, No. 2, 20.10.2006, p. 277-289.

Research output: Contribution to journal › Article

Roux, Isabelle ; Safieddine, Saaid ; Nouvian, Régis ; Grati, M'hamed ; Simmler, Marie Christine ; Bahloul, Amel ; Perfettini, Isabelle ; Le Gall, Morgane ; Rostaing, Philippe ; Hamard, Ghislaine ; Triller, Antoine ; Avan, Paul ; Moser, Tobias ; Petit, Christine. / Otoferlin, Defective in a Human Deafness Form, Is Essential for Exocytosis at the Auditory Ribbon Synapse. In: Cell. 2006 ; Vol. 127, No. 2. pp. 277-289.

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AU - Rostaing, Philippe

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N2 - 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.

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10.1016/j.cell.2006.08.040