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.
Pubmed ID: 17055430 RIS Download
Animals | Auditory Pathways | Calcium | Cochlea | Deafness | Evoked Potentials, Auditory, Brain Stem | Exocytosis | Hair Cells, Auditory, Inner | Humans | Membrane Fusion | Membrane Proteins | Mice | Mice, Inbred C57BL | Mice, Knockout | Synapses | Synaptic Transmission | Synaptic Vesicles | Synaptosomal-Associated Protein 25 | Syntaxin 1 | Time Factors