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

Nicolas Michalski, Juan D Goutman, Sarah Marie Auclair, Jacques Boutet de Monvel, Margot Tertrais, Alice Emptoz, Alexandre Parrin, Sylvie Nouaille, Marc Guillon, Martin Sachse, Danica Ciric, Amel Bahloul, Jean-Pierre Hardelin, Roger Bryan Sutton, Paul Avan, Shyam S Krishnakumar, James E Rothman, Didier Dulon, Saaid Safieddine, Christine Petit
eLife. 2017-11-07; 6:
DOI: 10.7554/elife.31013

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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.

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