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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acceleration
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Action Potentials / drug effects
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Action Potentials / physiology
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Analysis of Variance
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Animals
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Animals, Newborn
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Biophysics
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Calcium / metabolism*
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Calcium Channel Blockers / pharmacology
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Chelating Agents / pharmacology
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Egtazic Acid / analogs & derivatives
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Egtazic Acid / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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Exocytosis / drug effects
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Exocytosis / genetics
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Exocytosis / physiology*
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Hair Cells, Vestibular / classification
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Hair Cells, Vestibular / cytology*
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Hair Cells, Vestibular / drug effects
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Hair Cells, Vestibular / physiology
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Linear Models
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Membrane Proteins / deficiency
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Membrane Proteins / physiology*
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Mice
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Mice, Knockout
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Microscopy, Confocal
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Microscopy, Electron, Transmission
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Myosin VIIa
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Myosins / metabolism
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Patch-Clamp Techniques / methods
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Reaction Time / drug effects
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Reaction Time / physiology
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Receptors, AMPA / metabolism
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Synapses / drug effects
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Synapses / genetics
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Synapses / physiology*
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Synapses / ultrastructure
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Tetrodotoxin / pharmacology
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Vestibular Nerve / physiology
Substances
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Calcium Channel Blockers
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Chelating Agents
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Membrane Proteins
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Myo7a protein, mouse
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Myosin VIIa
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Receptors, AMPA
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otoferlin protein, mouse
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Tetrodotoxin
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Egtazic Acid
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Myosins
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1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
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glutamate receptor ionotropic, AMPA 2
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Calcium