RIM-binding proteins recruit BK-channels to presynaptic release sites adjacent to voltage-gated Ca2+-channels

EMBO J. 2018 Aug 15;37(16):e98637. doi: 10.15252/embj.201798637. Epub 2018 Jul 2.

Abstract

The active zone of presynaptic nerve terminals organizes the neurotransmitter release machinery, thereby enabling fast Ca2+-triggered synaptic vesicle exocytosis. BK-channels are Ca2+-activated large-conductance K+-channels that require close proximity to Ca2+-channels for activation and control Ca2+-triggered neurotransmitter release by accelerating membrane repolarization during action potential firing. How BK-channels are recruited to presynaptic Ca2+-channels, however, is unknown. Here, we show that RBPs (for RIM-binding proteins), which are evolutionarily conserved active zone proteins containing SH3- and FN3-domains, directly bind to BK-channels. We find that RBPs interact with RIMs and Ca2+-channels via their SH3-domains, but to BK-channels via their FN3-domains. Deletion of RBPs in calyx of Held synapses decreased and decelerated presynaptic BK-currents and depleted BK-channels from active zones. Our data suggest that RBPs recruit BK-channels into a RIM-based macromolecular active zone complex that includes Ca2+-channels, synaptic vesicles, and the membrane fusion machinery, thereby enabling tight spatio-temporal coupling of Ca2+-influx to Ca2+-triggered neurotransmitter release in a presynaptic terminal.

Keywords: BK‐channels; active zone; nano‐domain coupling; neurotransmitter release; voltage‐gated calcium channels.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Large-Conductance Calcium-Activated Potassium Channels / genetics
  • Large-Conductance Calcium-Activated Potassium Channels / metabolism*
  • Mice
  • Presynaptic Terminals / metabolism*
  • Synaptic Vesicles / genetics
  • Synaptic Vesicles / metabolism*
  • src Homology Domains

Substances

  • Calcium Channels
  • Large-Conductance Calcium-Activated Potassium Channels
  • Calcium