Instituto de Farmacologia e Neurociências e, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Br J Pharmacol. 2017 Dec;174(24):4725-4737. doi: 10.1111/bph.14051. Epub 2017 Nov 29.
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 and VPAC receptors. Presynaptic enhancement of GABA release contributes to VIP modulation of hippocampal synaptic transmission.
We investigated which VIP receptors and coupled transduction pathways were involved in VIP enhancement of K -evoked [ H]-GABA release from isolated nerve terminals of rat hippocampus.
VIP enhancement of [ H]-GABA release was potentiated in the presence of the VPAC receptor antagonist PG 97-269 but converted into an inhibition in the presence of the VPAC receptor antagonist PG 99-465, suggesting that activation of VPAC receptors inhibits and activation of VPAC receptors enhances, GABA release. A VPAC receptor agonist inhibited exocytotic voltage-gated calcium channel (VGCC)-dependent [ H]-GABA release through activation of protein G , an effect also dependent on PKC activity. A VPAC receptor agonist enhanced both exocytotic VGCC-dependent release through protein G -dependent, PKA-dependent and PKC-dependent mechanisms and GABA transporter 1-mediated [ H]-GABA release through a G protein-dependent and PKC-dependent mechanism.
Our results show that VPAC and VPAC VIP receptors have opposing actions on GABA release from hippocampal nerve terminals through activation of different transduction pathways. As VPAC and VPAC 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.
血管活性肠肽（VIP）是调节海马突触传递的重要调质，通过激活 VPAC 和 VPAC 受体，影响 GABA 能突触传递和谷氨酸能细胞兴奋性。突触前 GABA 释放增强有助于 VIP 调节海马突触传递。
我们研究了 VIP 增强大鼠海马分离神经末梢 K 诱发 [H]-GABA 释放涉及哪些 VIP 受体和偶联转导途径。
在 VPAC 受体拮抗剂 PG 97-269 存在的情况下，VIP 增强 [H]-GABA 释放，而在 VPAC 受体拮抗剂 PG 99-465 存在的情况下，VIP 增强 [H]-GABA 释放转换为抑制，表明 VPAC 受体激活抑制，VPAC 受体激活增强 GABA 释放。VPAC 受体激动剂通过激活蛋白 G 抑制外排电压门控钙通道（VGCC）依赖性 [H]-GABA 释放，这种作用也依赖于 PKC 活性。VPAC 受体激动剂通过蛋白 G 依赖性、PKA 依赖性和 PKC 依赖性机制增强外排 VGCC 依赖性释放和 GABA 转运体 1 介导的 [H]-GABA 释放，通过 G 蛋白依赖性和 PKC 依赖性机制增强外排 VGCC 依赖性释放。
我们的结果表明，VPAC 和 VPAC VIP 受体通过激活不同的转导途径对海马神经末梢 GABA 释放具有相反的作用。由于 VPAC 和 VPAC 受体位于 Ammon 角的不同层，我们的结果表明，这些 VIP 受体可能在调节向锥体神经元树突和胞体的突触传递方面存在差异，这对其在治疗癫痫方面的可能治疗应用具有重要意义。
