Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses
- Institut Pasteur, France
- Universidad de Buenos Aires, Argentina
- Yale University School of Medicine, United States
- UMRS 1120, Institut National de la Santé et de la Recherche Médicale (INSERM), France
- Université Paris Descartes, Sorbonne Paris Cité, France
- Texas Tech University Health Sciences Center, United States
- Université d'Auvergne, France
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.
Article and author information
Author details
Shyam S Krishnakumar
Funding
Foundation Raymonde et Guy Strittmatter (Research project grant)
- Christine Petit
Foundation BNP Parisbas (Research project grant)
- Christine Petit
LHW-Stiftung (Research project grant)
- Christine Petit
LabExLifesenses (ANR‐10‐LABX‐65)
- Christine Petit
Investissements d'Avenir (ANR‐11‐IDEX‐0004‐02)
- Christine Petit
Agir pour l'Audition (Prix Emergence scientifique)
- Nicolas Antoine Michalski
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Christian Rosenmund, Charité-Universitätsmedizin Berlin, Germany
Ethics
Animal experimentation: Animal experiments were carried out in accordance with European Community Council Directive 2010/63/UE under authorizations 2012-028, 2012-038, and 2014-005 from the Institut Pasteur ethics committee for animal experimentation.
Version history
- Received: August 11, 2017
- Accepted: November 6, 2017
- Accepted Manuscript published: November 7, 2017 (version 1)
- Version of Record published: November 23, 2017 (version 2)
Copyright
© 2017, Michalski et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses
eLife 6:e31013.
https://doi.org/10.7554/eLife.31013
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