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Background  Short-term presynaptic inhibition mediated by G protein-coupled receptors involves a direct interaction between G proteins and the vesicle release machinery. Recent studies implicate the C terminus of the vesicle-associated protein SNAP-25 as a molecular binding target of Gβγ that transiently reduces vesicular release. However, it is not known whether SNAP-25 is a target for molecular modifications expressing  long-term  changes in transmitter release probability.    Methodology/Principal Findings  This study utilized two-photon laser scanning microscopy for real-time imaging of action potential-evoked [Ca 2+ ] increases, in single Schaffer collateral presynaptic release sites in  in vitro  hippocampal slices, plus simultaneous recording of Schaffer collateral-evoked synaptic potentials. We used electroporation to infuse small peptides through CA3 cell bodies into presynaptic Schaffer collateral terminals to selectively study the presynaptic effect of scavenging the G-protein Gβγ. We demonstrate here that the C terminus of SNAP-25 is necessary for expression of LTD, but not long-term potentiation (LTP), of synaptic strength. Using type A botulinum toxin (BoNT/A) to enzymatically cleave the 9 amino acid C-terminus of SNAP-25 eliminated the ability of low frequency synaptic stimulation to induce LTD, but  not  LTP, even if release probability was restored to pre-BoNT/A levels by elevating extracellular [Ca 2+ ]. Presynaptic electroporation infusion of the 14-amino acid C-terminus of SNAP-25 (Ct-SNAP-25), to scavenge Gβγ, reduced both the transient presynaptic inhibition produced by the group II metabotropic glutamate receptor stimulation, and LTD. Furthermore, presynaptic infusion of mSIRK, a second, structurally distinct Gβγ scavenging peptide, also blocked the induction of LTD. While Gβγ binds directly to and inhibit voltage-dependent Ca 2+  channels, imaging of presynaptic [Ca 2+ ] with Mg-Green revealed that low-frequency stimulation only transiently reduced presynaptic Ca 2+  influx, an effect not altered by infusion of Ct-SNAP-25.    Conclusions/Significance  The C-terminus of SNAP-25, which links synaptotagmin I to the SNARE complex, is a binding target for Gβγ necessary for both transient transmitter-mediated presynaptic inhibition, and the induction of presynaptic LTD.

Gβγ and the C Terminus of SNAP-25 Are Necessary for Long-Term Depression of Transmitter Release