CAST/ELKS Proteins Control Voltage-Gated Ca 2+ Channel Density and Synaptic Release Probability at a Mammalian Central Synapse

Cell Rep. 2018 Jul 10;24(2):284-293.e6. doi: 10.1016/j.celrep.2018.06.024.

Abstract

In the presynaptic terminal, the magnitude and location of Ca2+ entry through voltage-gated Ca2+ channels (VGCCs) regulate the efficacy of neurotransmitter release. However, how presynaptic active zone proteins control mammalian VGCC levels and organization is unclear. To address this, we deleted the CAST/ELKS protein family at the calyx of Held, a CaV2.1 channel-exclusive presynaptic terminal. We found that loss of CAST/ELKS reduces the CaV2.1 current density with concomitant reductions in CaV2.1 channel numbers and clusters. Surprisingly, deletion of CAST/ELKS increases release probability while decreasing the readily releasable pool, with no change in active zone ultrastructure. In addition, Ca2+ channel coupling is unchanged, but spontaneous release rates are elevated. Thus, our data identify distinct roles for CAST/ELKS as positive regulators of CaV2.1 channel density and suggest that they regulate release probability through a post-priming step that controls synaptic vesicle fusogenicity.

Keywords: CAST/ELKS; active zone; auditory signaling; calcium channels; calyx of Held; exocytosis; release probability; synaptic transmission.

Publication types

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

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Calcium Channels, N-Type / metabolism*
  • Carrier Proteins / metabolism*
  • Cytoskeletal Proteins / deficiency
  • Cytoskeletal Proteins / metabolism*
  • Ion Channel Gating*
  • Kinetics
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / metabolism*
  • Neurotransmitter Agents / metabolism
  • Probability
  • Synapses / metabolism*
  • Synapses / ultrastructure
  • Synaptic Transmission / physiology
  • rab GTP-Binding Proteins

Substances

  • Calcium Channels, N-Type
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Erc2 protein, mouse
  • Nerve Tissue Proteins
  • Neurotransmitter Agents
  • Rab6ip2 protein, mouse
  • voltage-dependent calcium channel (P-Q type)
  • rab GTP-Binding Proteins