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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 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+ -channels or Ca 2+  uncaging. Otoferlin thus functions as a Ca 2+  sensor, setting the rates of primed vesicle fusion with the presynaptic plasma membrane and synaptic vesicle pool replenishment in the IHC active zone.

Otoferlin acts as a Ca 2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses