Gßy Competition with Syt1 for Binding to the SNARE Complex: Modulation of Exocytosis

Both 5-HT1B receptors and GABAB receptors are Gi/o GPCRs colocalized at CA1-subicular pyramidal cell synapses that act to inhibit neurotransmitter release. Presynaptic inhibition has previously been believed to result from a reduction of release probability (Pr) following inhibition of evoked Ca2+ entry. However, emerging evidence suggests GPCRs may inhibit neurotransmitter release independently of Ca2+ channel effects. While presynaptic GABAB receptors inhibit Ca2+ entry at CA1 terminals, 5-HT1B receptors also inhibit neurotransmission at CA1 terminals, but rather than alternating presynaptic Ca2+ concentrations, this action is mediated “downstream” of Ca2+ entry, by a direct targeting of Gβγ to the presynaptic release machinery. We now demonstrate that, whereas GABAB receptors alter Pr, activation of 5-HT1B receptors do not, but instead reduce the peak concentration of evoked glutamate in the cleft. This modulation of cleft glutamate concentration allows for differential effects on postsynaptic glutamate receptors, such that 5-HT1B receptors are much less effective at inhibiting NMDA receptor-mediated synaptic responses than those mediated by AMPA receptors. We also demonstrate that at the final hippocampal output, single synaptic responses are blocked, but short trains of activity, which allow a presynaptic accumulation of Ca2+, force frequency-dependent recovery of neurotransmitter release. Indeed, raised Ca2+ concentrations prevent 5-HT1B receptor-mediated inhibition, consistent with previous reports of a competition between Ca2+-synaptotagmin and G interactions with the SNARE complex. Thus, stimulus trains in 5-HT unveil a dynamic modulation of postsynaptic receptor activation and a sophisticated filter of hippocampal output.