VPAC 1 and VPAC 2 receptor activation on GABA release from hippocampal nerve terminals involve several different signalling pathways

Background and Purpose Vasoactive intestinal peptide (VIP) is an important modulator of hippocampal synaptic transmission that influences both GABAergic synaptic transmission and glutamatergic cell excitability through activation of VPAC 1 and VPAC 2 receptors. Presynaptic enhancement of GABA release contributes to VIP modulation of hippocampal synaptic transmission. Experimental Approach We investigated which VIP receptors and coupled transduction pathways were involved in VIP enhancement of K + ‐evoked [ 3 H]‐GABA release from isolated nerve terminals of rat hippocampus. Key Results VIP enhancement of [ 3 H]‐GABA release was potentiated in the presence of the VPAC 1 receptor antagonist PG 97‐269 but converted into an inhibition in the presence of the VPAC 2 receptor antagonist PG 99‐465, suggesting that activation of VPAC 1 receptors inhibits and activation of VPAC 2 receptors enhances, GABA release. A VPAC 1 receptor agonist inhibited exocytotic voltage‐gated calcium channel (VGCC)‐dependent [ 3 H]‐GABA release through activation of protein G i/o , an effect also dependent on PKC activity. A VPAC 2 receptor agonist enhanced both exocytotic VGCC‐dependent release through protein G s ‐dependent, PKA‐dependent and PKC‐dependent mechanisms and GABA transporter 1‐mediated [ 3 H]‐GABA release through a G s protein‐dependent and PKC‐dependent mechanism. Conclusions and Implications Our results show that VPAC 1 and VPAC 2 VIP receptors have opposing actions on GABA release from hippocampal nerve terminals through activation of different transduction pathways. As VPAC 1 and VPAC 2 receptors are located in different layers of Ammon's horn, our results suggest that these VIP receptors underlie different modulation of synaptic transmission to pyramidal cell dendrites and cell bodies, with important consequences for their possible therapeutic application in the treatment of epilepsy.