1. Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses.
- Author
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Michalski, Nicolas, Goutman, Juan D., Auclair, Sarah Marie, de Monvel, Jacques Boutet, 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, and Petit, Christine
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HAIR cells , *VESICLES (Cytology) , *AUDITORY perception , *CHIMERIC proteins , *SYNAPSES - Abstract
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 C2-domain, Ca2+-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 Ca2+-binding affinity of the C²C domain. The IHC ribbon synapse structure, synaptic Ca²+ currents, and otoferlin distribution were unaffected in these mutant mice, but auditory brainstem response wave-I amplitude was reduced. Lower Ca2+ sensitivity and delay of the fast and sustained components of synaptic exocytosis were revealed by membrane capacitance measurement upon modulations of intracellular Ca2+ concentration, by varying Ca2+ influx through voltage-gated Ca2+- channels or Ca2+ uncaging. Otoferlin thus functions as a Ca2+ sensor, setting the rates of primed vesicle fusion with the presynaptic plasma membrane and synaptic vesicle pool replenishment in the IHC active zone. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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