| Literature DB >> 29111973 |
Didier Dulon1,2, Saaid Safieddine3,1,4,5, Christine Petit3,1,4,6,7, Nicolas Michalski3,1,4, Juan D Goutman8, Sarah Marie Auclair9, Jacques Boutet de Monvel3,1,4, Margot Tertrais1,2, Alice Emptoz3,1,4, Alexandre Parrin3,1,4, Sylvie Nouaille3,1,4, Marc Guillon10, Martin Sachse11, Danica Ciric3,1,4, Amel Bahloul3,1,4,5, Jean-Pierre Hardelin3,1,4, Roger Bryan Sutton12,13, Paul Avan14,15,16, Shyam S Krishnakumar9,17, James E Rothman9,17.
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 (OtofAla515,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.Entities:
Keywords: deafness; inner hair cell; mouse; neuroscience; neurotransmitter release; synaptic exocytotic machinery; synaptopathy; temporal precision
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Year: 2017 PMID： 29111973 PMCID： PMC5700815 DOI： 10.7554/eLife.31013
Source DB: PubMed Journal: Elife ISSN： 2050-084X Impact factor: 8.140