title: Otoferlin is critical for a highly sensitive and linear calcium-dependent exocytosis at vestibular hair cell ribbon synapses.
abstract: Otoferlin, a C2-domain-containing Ca(2+) binding protein, is required for synaptic exocytosis in auditory hair cells. However, its exact role remains essentially unknown. Intriguingly enough, no balance defect has been observed in otoferlin-deficient (Otof(-/-)) mice. Here, we show that the vestibular nerve compound action potentials evoked during transient linear acceleration ramps in Otof(-/-) mice display higher threshold, lower amplitude, and increased latency compared with wild-type mice. Using patch-clamp capacitance measurement in intact utricles, we show that type I and type II hair cells display a remarkable linear transfer function between Ca(2+) entry, flowing through voltage-activated Ca(2+) channels, and exocytosis. This linear Ca(2+) dependence was observed when changing the Ca(2+) channel open probability or the Ca(2+) flux per channel during various test potentials. In Otof(-/-) hair cells, exocytosis displays slower kinetics, reduced Ca(2+) sensitivity, and nonlinear Ca(2+) dependence, despite morphologically normal synapses and normal Ca(2+) currents. We conclude that otoferlin is essential for a high-affinity Ca(2+) sensor function that allows efficient and linear encoding of low-intensity stimuli at the vestibular hair cell synapse.
authors.affiliation: Université Victor Segalen Bordeaux 2, Institut des Neurosciences de Bordeaux, Equipe Neurophysiologie de la Synapse Auditive, Inserm, Unité Mixte de Recherche en Santé 587, Centre Hospitalier Universitaire Hôpital Pellegrin, 33076 Bordeaux, France. didier.dulon@inserm.fr
authors.forename: Didier
authors.initials: D
authors.lastname: Dulon
authors.forename: Saaid
authors.initials: S
authors.lastname: Safieddine
authors.forename: Sherri M
authors.initials: SM
authors.lastname: Jones
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
mesh_terms: D000054:Acceleration; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005089:Exocytosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018069:Hair Cells, Vestibular / Q000145:classification / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D016014:Linear Models; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D000081412:Myosin VIIa; D009218:Myosins / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D013779:Tetrodotoxin / Q000494:pharmacology; D014725:Vestibular Nerve / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers; D002614:Chelating Agents; D008565:Membrane Proteins; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D018091:Receptors, AMPA; C516233:otoferlin protein, mouse; D013779:Tetrodotoxin; D004533:Egtazic Acid; D009218:Myosins; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium