Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse.
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.
Roux
Isabelle
I
Inserm UMRS587, Unité de Génétique des Déficits Sensoriels, Collège de France, Institut Pasteur, 25 rue du Dr Roux, 75015 Paris, France.
Safieddine
Saaid
S
Nouvian
Régis
R
Grati
M'hamed
M
Simmler
Marie-Christine
MC
Bahloul
Amel
A
Perfettini
Isabelle
I
Le Gall
Morgane
M
Rostaing
Philippe
P
Hamard
Ghislaine
G
Triller
Antoine
A
Avan
Paul
P
Moser
Tobias
T
Petit
Christine
C
D000818:Animals; D001306:Auditory Pathways / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003051:Cochlea / Q000254:growth & development / Q000378:metabolism*; D003638:Deafness / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016057:Evoked Potentials, Auditory, Brain Stem; D005089:Exocytosis; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008561:Membrane Fusion; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D050827:Syntaxin 1 / Q000378:metabolism; D013997:Time Factors
D008565:Membrane Proteins; C118457:OTOF protein, human; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D002118:Calcium