TY - JOUR
T1 - Otoferlin, Defective in a Human Deafness Form, Is Essential for Exocytosis at the Auditory Ribbon Synapse
AU - Roux, Isabelle
AU - Safieddine, Saaid
AU - Nouvian, Régis
AU - Grati, M'hamed
AU - Simmler, Marie Christine
AU - Bahloul, Amel
AU - Perfettini, Isabelle
AU - Le Gall, Morgane
AU - Rostaing, Philippe
AU - Hamard, Ghislaine
AU - Triller, Antoine
AU - Avan, Paul
AU - Moser, Tobias
AU - Petit, Christine
N1 - Funding Information:
In vitro hair cell physiology studies were carried out by R.N. We are grateful to Drs. Jean-Pierre Hardelin, Jacqueline Levilliers, Marc Poirot, and Sylvie Roux for their invaluable discussion and help and to Sonia Verp and all staff members of the intramural platforms for excellent technical assistance. We thank Dr. Richard Scheller for providing us with the SNARE plasmids, Drs. Elisabeth Verpy and Michel Leibovici for the cochlear library, and Dr Yvan Lallemand for Pgk-1 -cre mice. This work was supported by grants from the Foundation Louis-Jeantet and the French Ministry of Research (ACI “Biologie du Développement et Physiologie intégrative”) to C.P., the European Commission FP6 Integrated Project EuroHear LSHG-CT-2004-512063 to C.P and T.M., Human Frontiers Science Program to T.M. and S.S., and the Deutsche Forschungsgemeinschaft to T.M. (Center for Molecular Physiology of the Brain). I.R. is a MENRT grant holder.
PY - 2006/10/20
Y1 - 2006/10/20
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.
AB - 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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U2 - 10.1016/j.cell.2006.08.040
DO - 10.1016/j.cell.2006.08.040
M3 - Article
C2 - 17055430
AN - SCOPUS:33749994043
VL - 127
SP - 277
EP - 289
JO - Cell
JF - Cell
SN - 0092-8674
IS - 2
ER -