Differential triggering of spontaneous glutamate release by P/Q-, N- and R-type Ca2+ channels

Nat Neurosci. 2013 Dec;16(12):1754-1763. doi: 10.1038/nn.3563. Epub 2013 Nov 3.


The role of voltage-gated Ca2+ channels (VGCCs) in spontaneous miniature neurotransmitter release is incompletely understood. We found that stochastic opening of P/Q-, N- and R-type VGCCs accounts for ∼50% of all spontaneous glutamate release at rat cultured hippocampal synapses, and that R-type channels have a far greater role in spontaneous than in action potential-evoked exocytosis. VGCC-dependent miniature neurotransmitter release (minis) showed similar sensitivity to presynaptic Ca2+ chelation as evoked release, arguing for direct triggering of spontaneous release by transient spatially localized Ca(2+) domains. Experimentally constrained three-dimensional diffusion modeling of Ca2+ influx-exocytosis coupling was consistent with clustered distribution of VGCCs in the active zone of small hippocampal synapses and revealed that spontaneous VGCCs openings can account for the experimentally observed VGCC-dependent minis, although single channel openings triggered release with low probability. Uncorrelated stochastic VGCC opening is therefore a major trigger for spontaneous glutamate release, with differential roles for distinct channel subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Calcium / metabolism
  • Calcium Channel Agonists / pharmacology
  • Calcium Channel Blockers
  • Calcium Channels / classification*
  • Calcium Channels / physiology*
  • Cells, Cultured
  • Chelating Agents / pharmacology
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Electric Stimulation
  • Excitatory Postsynaptic Potentials / drug effects
  • Glutamic Acid / metabolism*
  • Hippocampus / cytology
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology*
  • Models, Biological
  • Neurons / drug effects
  • Neurons / metabolism*
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Stochastic Processes


  • Calcium Channel Agonists
  • Calcium Channel Blockers
  • Calcium Channels
  • Chelating Agents
  • Glutamic Acid
  • Egtazic Acid
  • EGTA acetoxymethyl ester
  • 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
  • Calcium