Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse
Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse
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DOI：
10.1016/j.cell.2006.08.040
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发表时间：
2006-10-20
期刊：
影响因子：
64.5
通讯作者：
Petit, Christine
中科院分区：
文献类型：
--
作者：
Roux, Isabelle;Safieddine, Saaid;Petit, Christine
听觉内毛细胞 (IHC) 带状突触以卓越的时间精度运行，并保持高水平的神经递质释放。然而，IHC 突触胞吐作用的分子机制在很大程度上尚不清楚。我们研究了 otoferlin，一种预测的 C2 结构域跨膜蛋白，它在人类隐性耳聋中存在缺陷。我们发现毛细胞中的 otoferlin 表达与传入突触发生相关，并发现 otoferlin 定位于带状相关突触小泡。 Otoferlin 结合 Ca2+ 并显示与 SNARE 蛋白 Syntaxin1 和 SNAP25 的 Ca2+ 依赖性相互作用。 Otoferlin 缺陷小鼠 (Otof(-/-)) 严重失聪。尽管带状突触形态发生和 Ca2+ 电流正常，但 Otof(-/-) IHC 中的胞吐作用几乎完全消失。因此，otoferlin 对于突触小泡胞吐作用的后期步骤至关重要，并且可能充当触发 IHC 带状突触处膜融合的主要 Ca2+ 传感器。
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 synapto-genesis 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.