Differential triggering of spontaneous glutamate release by P/Q-, N-, and R-type Ca(2+) channels

The role of voltage-gated Ca(2+) channels (VGCCs) in spontaneous miniature neurotransmitter release is incompletely understood. Here we show 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 play a far greater role in spontaneous than in action potential-evoked exocytosis. VGCC-dependent ‘minis’ show similar sensitivity to presynaptic Ca(2+) 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 Ca(2+) influx-exocytosis coupling is consistent with clustered distribution of VGCCs in the active zone of small hippocampal synapses, and shows that spontaneous VGCCs openings can account for the experimentally observed VGCC-dependent minis, although single channel openings trigger release with low probability. Uncorrelated stochastic VGCC opening is thus a major trigger for spontaneous glutamate release, with differential roles for distinct channel subtypes.