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

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

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UCL Institute of Neurology, University College London, Queen Square, WC1N 3BG, United Kingdom.
Department of Computer Science, University of Warwick, Coventry, CV4 7AL, United Kingdom.
Centre for Complexity Science, University of Warwick, Coventry, CV4 7AL, United Kingdom.
Contributed equally


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.

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