Cell Reports
Volume 25, Issue 12, 18 December 2018, Pages 3451-3464.e3
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Article
Clustered Ca2+ Channels Are Blocked by Synaptic Vesicle Proton Release at Mammalian Auditory Ribbon Synapses

https://doi.org/10.1016/j.celrep.2018.11.072Get rights and content
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Highlights

  • A proton-mediated Ca2+ current transient block (ICaTB) occurs at hair cell synapses

  • ICaTB is absent from immature inner hair cell synapses with non-compact active zones

  • ICaTB has a multi-peak structure that is eliminated in otoferlin-KO mice

  • ICaTB may contribute significantly to fast in vivo spike adaptation at afferent fibers

Summary

A Ca2+ current transient block (ICaTB) by protons occurs at some ribbon-type synapses after exocytosis, but this has not been observed at mammalian hair cells. Here we show that a robust ICaTB occurs at post-hearing mouse and gerbil inner hair cell (IHC) synapses, but not in immature IHC synapses, which contain non-compact active zones, where Ca2+ channels are loosely coupled to the release sites. Unlike ICaTB at other ribbon synapses, ICaTB in mammalian IHCs displays a surprising multi-peak structure that mirrors the EPSCs seen in paired recordings. Desynchronizing vesicular release with intracellular BAPTA or by deleting otoferlin, the Ca2+ sensor for exocytosis, greatly reduces ICaTB, whereas enhancing release synchronization by raising Ca2+ influx or temperature increases ICaTB. This suggests that ICaTB is produced by fast multivesicular proton-release events. We propose that ICaTB may function as a submillisecond feedback mechanism contributing to the auditory nerve’s fast spike adaptation during sound stimulation.

Keywords

Ca2+ channels
pH buffering
protons
inner hair cells
ribbon synapses
exocytosis
otoferlin
auditory nerve fiber

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