Differential triggering of spontaneous glutamate release by P/Q-, N- and R-type [Ca.sup.2+] channels

The role of voltage-gated [Ca.sup.2+] 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 [Ca.sup.2+] chelation as evoked release, arguing for direct triggering of spontaneous release by transient spatially localized [Ca.sup.2+] domains. Experimentally constrained three-dimensional diffusion modeling of [Ca.sup.2+] 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.