1. Otoferlin acts as a Ca 2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses.
- Author
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Michalski N, Goutman JD, Auclair SM, Boutet de Monvel J, Tertrais M, Emptoz A, Parrin A, Nouaille S, Guillon M, Sachse M, Ciric D, Bahloul A, Hardelin JP, Sutton RB, Avan P, Krishnakumar SS, Rothman JE, Dulon D, Safieddine S, and Petit C
- Subjects
- Animals, Calcium metabolism, Gene Knock-In Techniques, Membrane Proteins genetics, Mice, Protein Binding, Receptors, Calcium-Sensing genetics, Hair Cells, Auditory physiology, Membrane Fusion, Membrane Proteins metabolism, Receptors, Calcium-Sensing metabolism, Synapses physiology, Synaptic Vesicles metabolism
- 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 C
2 -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 C2 C 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.- Published
- 2017
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