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Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses

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Michalski, Nicolas | Goutman, Juan D | Auclair, Sarah Marie | Boutet de Monvel, Jacques | Tertrais, Margot | Emptoz, Alice | Parrin, Alexandre | Nouaille, Sylvie | Guillon, Marc | Sachse, Martin | Ciric, Danica | Bahloul, Amel | Hardelin, Jean-Pierre | Sutton, Roger Bryan | Avan, Paul | Krishnakumar, Shyam S | Rothman, James E | Dulon, Didier | Safieddine, Saaid | Petit, Christine

Edité par CCSD ; eLife Sciences Publication -

International audience. Hearing relies on rapid, temporally precise, and sustained neurotransmitter release at the ribbon synapses of sensory cells, the inner hair cells (IHCs). This process requires otoferlin, a six C 2-domain, Ca 2+-binding transmembrane protein of synaptic vesicles. To decipher the role of otoferlin in the synaptic vesicle cycle, we produced knock-in mice (Otof Ala515,Ala517/Ala515,Ala517) with lower Ca 2+-binding affinity of the C 2 C domain. The IHC ribbon synapse structure, synaptic Ca 2+ currents, and otoferlin distribution were unaffected in these mutant mice, but auditory brainstem response wave-I amplitude was reduced. Lower Ca 2+ sensitivity and delay of the fast and sustained components of synaptic exocytosis were revealed by membrane capacitance measurement upon modulations of intracellular Ca 2+ concentration, by varying Ca 2+ influx through voltage-gated Ca 2+-Michalski et al. eLife 2017;6:e31013.

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