Vasoactive intestinal peptide acts via multiple signal pathways to regulate hippocampal NMDA receptors and synaptic transmission.
Yang. Kai K; Trepanier. Catherine H CH; Li. Hongbin H; Beazely. Michael A MA; Lerner. Ethan A EA; Jackson. Michael F MF; MacDonald. John F JF
Key Findings
- 1 nM VIP enhances NMDA currents via VPAC receptors and the cAMP/PKA pathway, requiring AKAP scaffolding.
- The VPAC antagonist GRF‑1‑29 blocks the low‑dose VIP effect on NMDA receptors.
- 100 nM VIP activates PAC1 receptors and Src kinase, not the PKA pathway.
Practical Outcomes
- For biohackers, the data suggest that low‑dose VIP might improve synaptic plasticity, but using GRF‑1‑29 would likely negate that benefit. No clear dosing or protocol emerges, and the peptide appears more useful as a research tool than a performance enhancer.
Summary
The study shows that a tiny amount of the hormone VIP can boost brain cell communication (NMDA receptors) through specific VPAC receptors and a cAMP/PKA signaling route, while a higher dose uses a different receptor (PAC1) and other pathways. The peptide GRF‑1‑29 blocks the VPAC‑mediated boost, meaning it can stop this effect.
Abstract
Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide, which belongs to a superfamily of structurally related peptide hormones including 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 including the PACAP receptor (PAC1-R) and the two VIP receptors (VPAC receptors). VIP can activate the PAC1-R 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. Our lab has showed that PAC1-R activation signals through PKC/CAKbeta/Src pathway to regulate NMDA receptors; however, there is little known about the potential regulation of NMDA receptors by VPAC receptors. Our studies demonstrated that application of 1 nM VIP enhanced NMDA currents by stimulating the VPAC receptors as the effect was blocked by VPAC receptor antagonist [Ac-Tyr(1), D-Phe(2)]GRF (1-29). This enhancement of NMDA currents was blocked by both Rp-cAMPS and PKI(14-22) (they are highly specific PKA inhibitors), but not by the specific PKC inhibitor, bisindolylmaleimide I. In addition, the VIP-induced enhancement of NMDA currents was accentuated by inhibition of phosphodiesterase 4, which inhibits the degradation of cAMP. This regulation of NMDA receptors also required the scaffolding protein AKAP. In contrast, the potentiation induced by high concentration of VIP (e.g., 100 nM) was mediated by PAC1-R as well as by Src kinase. Overall, these results show that VIP can regulate NMDA receptors through different receptors and signaling pathways.
Study Information
pubmed
2009
2009-09-01T00:00:00.000Z
10.1002/hipo.20559
44
52