Second messenger cascades involving G proteins1,2 and calcium3 are known to modulate neurotransmitter release4,5. A prominent effect of such a cascade is the downmodulation of presynaptic calcium influx6,7, which markedly reduces evoked neurotransmitter release5,7,8. Here we show that G-protein-mediated signalling, such as through GABA (γ-amino butyric acid) subtype B (GABAB) receptors, retards the recruitment of synaptic vesicles during sustained activity and after short-term depression. This retardation occurs through a lowering of cyclic AMP, which blocks the stimulatory effect of increased calcium concentration on vesicle recruitment. In this signalling pathway, cAMP (functioning through the cAMP-dependent guanine nucleotide exchange factor) and calcium/calmodulin cooperate to enhance vesicle priming. The differential modulation of the two forms of synaptic plasticity, presynaptic inhibition and calcium-dependent recovery from synaptic depression, is expected to have interesting consequences for the dynamic behaviour of neural networks.
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We thank N. Brose, F. Felmy, C. Rosenmund, F. Sachs, R. Schneggenburger, G. Schultz and M. Wölfel for critical comments on the manuscript. This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (DFG Research Center on Molecular Physiology of the Brain).
The authors declare that they have no competing financial interests.
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Sakaba, T., Neher, E. Direct modulation of synaptic vesicle priming by GABAB receptor activation at a glutamatergic synapse. Nature 424, 775–778 (2003). https://doi.org/10.1038/nature01859
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