Retrograde Synaptic Inhibition Is Mediated by α-Neurexin Binding to the α2δ Subunits of N-Type Calcium Channels

Neuron. 2017 Jul 19;95(2):326-340.e5. doi: 10.1016/j.neuron.2017.06.018. Epub 2017 Jun 29.

Abstract

The synaptic adhesion molecules Neurexin and Neuroligin alter the development and function of synapses and are linked to autism in humans. In C. elegans, post-synaptic Neurexin (NRX-1) and pre-synaptic Neuroligin (NLG-1) mediate a retrograde synaptic signal that inhibits acetylcholine (ACh) release at neuromuscular junctions. Here, we show that the retrograde signal decreases ACh release by inhibiting the function of pre-synaptic UNC-2/CaV2 calcium channels. Post-synaptic NRX-1 binds to an auxiliary subunit of pre-synaptic UNC-2/CaV2 channels (UNC-36/α2δ), decreasing UNC-36 abundance at pre-synaptic elements. Retrograde inhibition is mediated by a soluble form of NRX-1's ectodomain, which is released from the post-synaptic membrane by the SUP-17/ADAM10 protease. Mammalian Neurexin-1α binds α2δ-3 and decreases CaV2.2 current in transfected cells, whereas Neurexin-1α has no effect on CaV2.2 reconstituted with α2δ-1 and α2δ-2. Collectively, these results suggest that α-Neurexin binding to α2δ is a conserved mechanism for regulating synaptic transmission.

Keywords: C. elegans; CACNA2D; Mef2; Neurexin; Neuroligin; autism; calcium channel; synaptic transmission.

MeSH terms

  • Acetylcholine / metabolism
  • Animals
  • Biophysical Phenomena / physiology*
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / metabolism
  • Calcium Channels, N-Type / metabolism*
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Glycoproteins / metabolism*
  • Humans
  • Nerve Tissue Proteins / metabolism
  • Neuromuscular Junction / metabolism
  • Neuropeptides / metabolism*
  • Protein Subunits / metabolism
  • Synapses / metabolism*
  • Synaptic Transmission / physiology*

Substances

  • Caenorhabditis elegans Proteins
  • Calcium Channels, N-Type
  • Cell Adhesion Molecules, Neuronal
  • Glycoproteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • Protein Subunits
  • neurexophilin
  • Acetylcholine