Philippe Vincent

Spatial organization of the Cav1.3 channels underly the exocytosis efficiency of hair cell ribbon synapses in the inner ear

Defended on December 16, 2015

La thèse de Philippe Vincent a été financée par une bourse au mérite de l’Ecole Doctorale des Sciences de la Vie et de la Santé, Université de Bordeaux.

 Spatial organization of the Cav1.3 channels underly the exocytosis efficiency of hair cell ribbon synapses in the inner ear

Abstract: Cochlear inner hair cells (IHCs) encode acoustic signals into nerve impulses at their ribbon synapses formed with the auditory afferent fibers. The exocytosis of glutamatergic vesicles is triggered by voltage activation of Cav1.3 channels and requires otoferlin, the putative intracellular Ca2+ sensor. The precise molecular mechanisms of exocytosis still remain elusive, notably the mechanisms allowing the temporal precision, the high rates of vesicular fusion (high frequency phase-locking with sound) and the indefatigability of the process.

We show here that exocytosis in auditory and vestibular hair cells relies on a specific tight spatial organization of Cav1.3 channels at the active zones. Auditory IHCs use different Cav1.3 isoforms, notably short C-terminal isoforms (Cav1.343S et Cav1.342A). These short Cav1.3 isoforms essentially trigger the RRP exocytosis (Readily Releasable Pool of vesicles) and are at the origin of its fast adaptation. This fast exocytotic adaptation is based both on an intracellular Ca2+ dependant inactivation of the Ca2+ current and on its extracellular block by exocytosed protons. Long Cav1.3 isoforms (Cav1.342L et Cav1.3D44) regulate the vesicular recruitment at the active zones. Furthermore, our results show that a synaptic actin cytoskeleton is essential for the tight spatial organization of the Cav1.3 channels at the ribbons. Clarin 1 (Usher IIIA protein), through its interactions with the F-actin network, harmonin (PDZ protein, Usher IC) and the Ca2+ channel β2 subunit, is required to maintain the tight organization of Cav1.3 channels at the ribbon synapses.

Keywords : Audition; Balance; Hair cells; Synaptic transmission; Otoferlin; Cav1.3 channels, Ribbon synapses; Usher Syndrom

 

 Publications

Synaptic F-actin network controls otoferlin-dependent exocytosis in auditory inner hair cells.
Vincent PF, Bouleau Y, Petit C, Dulon D.
Elife. 2015 Nov 14;4. pii: e10988. doi: 10.7554/eLife.10988.

Exocytotic machineries of vestibular type I and cochlear ribbon synapses display similar intrinsic otoferlin-dependent Ca2+ sensitivity but a different coupling to Ca2+ channels.
Vincent PF, Bouleau Y, Safieddine S, Petit C, Dulon D.
J Neurosci. 2014 Aug 13;34(33):10853-69. doi: 10.1523/JNEUROSCI.0947-14.2014.

 

Jury

  • Stéphane OLIET
    DR CNRS – Université de Bordeaux – Président
  • Christian CHABBERT
    CR CNRS – Université Aix Marseille – Rapporteur
  • Serge PICAUD
    DR INSERM – Institut de la vision – Rapporteur
  • Saaid SAFIEDDINE
    DR CNRS – Institut Pasteur – Examinateur
  • Didier DULON
    DR INSERM – Université de Bordeaux – Directeur de thèse

PhD supervisor

Didier Dulon
Directeur de recherche Inserm

Laboratoire de Neurophysiologie de la Synapse Auditive
INSERM U1120
Université de Bordeaux
Hôpital Pellegrin

Publications

Last update: 5 April 2018