Clustered Ca 2+ Channels Are Blocked by Synaptic Vesicle Proton Release at Mammalian Auditory Ribbon Synapses

Cell Rep. 2018 Dec 18;25(12):3451-3464.e3. doi: 10.1016/j.celrep.2018.11.072.


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: Ca(2+) channels; auditory nerve fiber; exocytosis; inner hair cells; otoferlin; pH buffering; protons; ribbon synapses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Calcium Channels / metabolism*
  • Cochlear Nerve / drug effects
  • Cochlear Nerve / physiology
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Exocytosis / drug effects
  • Gerbillinae
  • Hair Cells, Auditory / drug effects
  • Hair Cells, Auditory / metabolism*
  • Hair Cells, Auditory, Inner / drug effects
  • Hair Cells, Auditory, Inner / metabolism
  • Ion Channel Gating / drug effects
  • Mammals / metabolism*
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Models, Biological
  • Nifedipine / pharmacology
  • Protons*
  • Rana catesbeiana
  • Synaptic Vesicles / metabolism*
  • Temperature


  • Calcium Channels
  • Membrane Proteins
  • Protons
  • otoferlin protein, mouse
  • Egtazic Acid
  • Nifedipine
  • 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid