Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses
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 th...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/31013 |
| id |
doaj-0573827227564a46bbf876f5400e53e1 |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Nicolas Michalski Juan D Goutman Sarah Marie Auclair Jacques Boutet de Monvel Margot Tertrais Alice Emptoz Alexandre Parrin Sylvie Nouaille Marc Guillon Martin Sachse Danica Ciric Amel Bahloul Jean-Pierre Hardelin Roger Bryan Sutton Paul Avan Shyam S Krishnakumar James E Rothman Didier Dulon Saaid Safieddine Christine Petit |
| spellingShingle |
Nicolas Michalski Juan D Goutman Sarah Marie Auclair Jacques Boutet de Monvel Margot Tertrais Alice Emptoz Alexandre Parrin Sylvie Nouaille Marc Guillon Martin Sachse Danica Ciric Amel Bahloul Jean-Pierre Hardelin Roger Bryan Sutton Paul Avan Shyam S Krishnakumar James E Rothman Didier Dulon Saaid Safieddine Christine Petit Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses eLife deafness neurotransmitter release synaptic exocytotic machinery synaptopathy temporal precision inner hair cell |
| author_facet |
Nicolas Michalski Juan D Goutman Sarah Marie Auclair Jacques Boutet de Monvel Margot Tertrais Alice Emptoz Alexandre Parrin Sylvie Nouaille Marc Guillon Martin Sachse Danica Ciric Amel Bahloul Jean-Pierre Hardelin Roger Bryan Sutton Paul Avan Shyam S Krishnakumar James E Rothman Didier Dulon Saaid Safieddine Christine Petit |
| author_sort |
Nicolas Michalski |
| title |
Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses |
| title_short |
Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses |
| title_full |
Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses |
| title_fullStr |
Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses |
| title_full_unstemmed |
Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses |
| title_sort |
otoferlin acts as a ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses |
| publisher |
eLife Sciences Publications Ltd |
| series |
eLife |
| issn |
2050-084X |
| publishDate |
2017-11-01 |
| description |
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 (Otof Ala515,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. |
| topic |
deafness neurotransmitter release synaptic exocytotic machinery synaptopathy temporal precision inner hair cell |
| url |
https://elifesciences.org/articles/31013 |
| work_keys_str_mv |
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1721460452023599104 |
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doaj-0573827227564a46bbf876f5400e53e12021-05-05T13:55:11ZengeLife Sciences Publications LtdeLife2050-084X2017-11-01610.7554/eLife.31013Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapsesNicolas Michalski0https://orcid.org/0000-0002-1287-2709Juan D Goutman1Sarah Marie Auclair2Jacques Boutet de Monvel3https://orcid.org/0000-0001-6182-3527Margot Tertrais4Alice Emptoz5Alexandre Parrin6Sylvie Nouaille7Marc Guillon8Martin Sachse9Danica Ciric10https://orcid.org/0000-0002-0098-6258Amel Bahloul11https://orcid.org/0000-0001-7042-4616Jean-Pierre Hardelin12https://orcid.org/0000-0002-1815-7909Roger Bryan Sutton13Paul Avan14Shyam S Krishnakumar15https://orcid.org/0000-0001-6148-3251James E Rothman16https://orcid.org/0000-0001-8653-8650Didier Dulon17Saaid Safieddine18https://orcid.org/0000-0002-6159-0572Christine Petit19https://orcid.org/0000-0002-9069-002XUnité de Génétique et Physiologie de l’Audition, Institut Pasteur, Paris, France; UMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France; Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, Paris, FranceInstituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, ArgentinaDepartment of Cell Biology, Yale University School of Medicine, New Haven, United StatesUnité de Génétique et Physiologie de l’Audition, Institut Pasteur, Paris, France; UMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France; Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, Paris, FranceUMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France; Laboratoire de Neurophysiologie de la Synapse Auditive, Bordeaux Neurocampus, Université de Bordeaux, Bordeaux, FranceUnité de Génétique et Physiologie de l’Audition, Institut Pasteur, Paris, France; UMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France; Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, Paris, FranceUnité de Génétique et Physiologie de l’Audition, Institut Pasteur, Paris, France; UMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France; Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, Paris, FranceUnité de Génétique et Physiologie de l’Audition, Institut Pasteur, Paris, France; UMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France; Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, Paris, FranceWave Front Engineering Microscopy Group, Neurophotonics Laboratory, Centre National de la Recherche Scientifique, UMR 8250, University Paris Descartes, Sorbonne Paris Cité, Paris, FranceCenter for Innovation & Technological Research, Ultrapole, Institut Pasteur, Paris, FranceUnité de Génétique et Physiologie de l’Audition, Institut Pasteur, Paris, France; UMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France; Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, Paris, FranceUnité de Génétique et Physiologie de l’Audition, Institut Pasteur, Paris, France; UMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France; Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, Paris, France; Centre National de la Recherche Scientifique, FranceUnité de Génétique et Physiologie de l’Audition, Institut Pasteur, Paris, France; UMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France; Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, Paris, FranceDepartment of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, United States; Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, United StatesLaboratoire de Biophysique Sensorielle, Université Clermont Auvergne, Clermont-Ferrand, France; UMR 1107, Institut National de la Santé et de la Recherche Médicale, Clermont-Ferrand, France; Centre Jean Perrin, Clermont-Ferrand, FranceDepartment of Cell Biology, Yale University School of Medicine, New Haven, United States; Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United KingdomDepartment of Cell Biology, Yale University School of Medicine, New Haven, United States; Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United KingdomUMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France; Laboratoire de Neurophysiologie de la Synapse Auditive, Bordeaux Neurocampus, Université de Bordeaux, Bordeaux, FranceUnité de Génétique et Physiologie de l’Audition, Institut Pasteur, Paris, France; UMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France; Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, Paris, France; Centre National de la Recherche Scientifique, FranceUnité de Génétique et Physiologie de l’Audition, Institut Pasteur, Paris, France; UMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France; Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, Paris, France; Syndrome de Usher et Autres Atteintes Rétino-Cochléaires, Institut de la Vision, Paris, France; Collège de France, Paris, FranceHearing 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 (Otof Ala515,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.https://elifesciences.org/articles/31013deafnessneurotransmitter releasesynaptic exocytotic machinerysynaptopathytemporal precisioninner hair cell |