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 | |
| State | Published - Oct 20 2006 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
Cite this
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
}
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
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.
UR - http://www.scopus.com/inward/record.url?scp=33749994043&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33749994043&partnerID=8YFLogxK
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 -