| Abstract No.: | A-B1073 |
| Country: | Canada |
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| Title: | THE MECHANISM OF NMDA RECEPTORS BY VASOACTIVE INTESTINAL PEPTIDE (VIP) IN HIPPOCAMPAL NEURONS |
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| Authors/Affiliations: | 1 Kai Yang*; 1 Catherine Trepanier; 1 Michael F. Jackson; 1 John F. MacDonald;
1 University of Toronto, ON, Canada
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| Content: | Vasoactive intestinal peptide (VIP) is a 28 amino acid peptide, which plays an important role in neuronal survival and development of the central and peripheral nervous systems. It has been shown to act as a neuromodulator, as a neurotrophic factor and as a neurotransmitter. VIP belongs to a member of a superfamily of structurally related peptide hormones that stimulate PKA and includes pituitary adenylate cyclase-activating polypeptide (PACAP). Although several studies have identified the involvement of PACAP in learning and memory, little work has been done to investigate such a role for VIP. At least three receptors for VIP have been identified. They include the PACAP receptor (PAC1-R), which exhibits a higher affinity for PACAP than VIP and the VIP receptors, VPAC1-R and VPAC2-R, which have similar affinities for PACAP and VIP. Previous studies in our laboratory showed that PACAP acts via the PAC-1R to enhance N-methyl-D-aspartate (NMDA)-evoked currents in CA1 hippocampal neurons as well as EPSCs mediated by NMDA receptors. Surprisingly, it does so by stimulating a sequential Gq/PKC/Pyk2/Src signal transduction cascade rather than by stimulating Gs, adenylate cyclase and PKA. There is little known about the potential regulation of NMDA receptors by VPAC receptors. VIP can activate the PAC-1R only if it is used at relatively high concentrations (e.g. 100 nM); however, at lower concentrations (e.g. 1 nM) it is selective for the VPAC receptors. CA1 pyramidal neurons were acutely isolated from young adult rat slices by mild enzymatic digestion. Neurons were subjected to whole cell voltage-clamp and responses to applications of NMDA recorded using a rapid perfusion system. Initially we found that a high concentration of VIP (100 nM) potentiated peak NMDA-evoked currents; however, this effect was blocked by a highly selective PAC1-R antagonist, M65, and by inhibitors of the PKC/Src signal pathway. These findings illustrate that at this concentration of VIP (100 nM), the predominant action of VIP is not mediated by VPAC receptors. In contrast, application of the lower concentration of VIP (1 nM) also enhanced NMDA receptor peak currents and it did so by stimulating VPAC receptors as the effect was blocked by [Ac-Tyr1,D-Phe2]GRF 1-29 (a specific VPAC antagonist). The enhancement of NMDA currents induced by low concentration of VIP was also blocked by Rp-cAMPS (a specific cAMP inhibitor) and by PKI14-22 (a highly specific PKA inhibitor), but not by the specific PKC inhibitor, bisindolylmaleimide I. In addition, the VIP-induced enhancement of NMDA-evoked currents was accentuated by application of a phosphodiesterase 4 inhibitor, which inhibits the degradation of cAMP. This regulation of NMDA receptors also required the scaffolding protein AKAP since the specific AKAP inhibitor, Ht31, also blocked the VIP-induced potentiation. Overall, these results show that VPAC receptors enhance NMDA-evoked currents via a cAMP/PKA signalling pathway. This work implicates VAPAC receptors as regulators of PKA and NMDA receptors and thereby suggests that |
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