| First Author | Michalski N | Year | 2017 |
| Journal | Elife | Volume | 6 |
| PubMed ID | 29111973 | Mgi Jnum | J:254993 |
| Mgi Id | MGI:6110937 | Doi | 10.7554/eLife.31013 |
| Citation | Michalski N, et al. (2017) Otoferlin acts as a Ca(2+) sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses. Elife 6:e31013 |
| abstractText | 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, 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 C2C 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. |
