Interaction of growth hormone-releasing factor (GRF) and 14 GRF analogs with vasoactive intestinal peptide (VIP) receptors of rat pancreas. Discovery of (N-Ac-Tyr1,D-Phe2)-GRF(1-29)-NH2 as a VIP antagonist.
Waelbroeck. M M; Robberecht. P P; Coy. D H DH; Camus. J C JC; De Neef. P P; Christophe. J J
Key Findings
- GRF‑1‑29 and 14 analogs can interfere with VIP binding to pancreatic receptors.
- (N‑Ac‑Tyr1,D‑Phe2)‑GRF(1‑29)‑NH2 uniquely blocks both VIP‑ and GRF‑stimulated adenylate cyclase, acting as a VIP antagonist.
- Modifications at positions 6 and 7 dramatically lower receptor affinity, whereas changes at positions 1‑4 have little effect.
- Acetylating the N‑terminus or using D‑amino acids at positions 3, 4, 6, or 7 reduces intrinsic activity; some D‑substitutions (e.g., D‑Ala2, Phe4) can create super‑agonists.
Practical Outcomes
- For biohackers, the work suggests that not all GRF‑1‑29 analogs are equal—some may also block VIP receptors, which could affect pancreatic function or metabolism. When choosing a GRF supplement, prefer formulations that avoid the specific modifications identified as VIP antagonists, unless you specifically want that effect. The findings are mainly mechanistic, so they don’t change dosing protocols but highlight potential off‑target actions to watch for.
Summary
The study shows that the natural growth‑hormone‑releasing factor (GRF‑1‑29) and several modified versions can bind to the same receptors that the hormone VIP uses in the rat pancreas. One specially modified peptide, (N‑Ac‑Tyr1,D‑Phe2)‑GRF(1‑29)‑NH2, blocks both VIP and GRF actions, acting like a VIP antagonist. Changing certain amino‑acid positions (especially 6 and 7) or swapping them for D‑forms makes the peptides less effective at stimulating the cell’s adenylate‑cyclase enzyme, while other swaps can make them even more active.
Abstract
Adenylate cyclase stimulation by GH-releasing factor (GRF) and 14 GRF analogs (modified in the N-terminal part) was compared to the capacity of the same peptides to inhibit [125I]iodo-vasoactive intestinal peptide (VIP) binding in rat pancreatic plasma membranes. These peptides interfered with VIP receptors as they inhibited [125I]iodo-VIP binding, and probably acted through VIP-preferring receptors as one of these peptides [(N-Ac-Tyr1,D-Phe2)-GRF(1-29)-NH2] selectively inhibited both VIP- and GRF-stimulated adenylate cyclase activities. In general, alterations in positions 6 and 7 (but not in positions 1-4) markedly reduced the affinity of the resulting GRF analog [based on Kact (concentration exerting half-maximal stimulation) values]. The intrinsic activity exerted by GRF analogs on adenylate cyclase was reduced by acetylation of the free NH2 group and by the replacement of Asp3, Ala4, Phe6, and Thr7 by the corresponding D-isomer. The presence of pCl-Phe6 and Trp6 also depressed this parameter. Substitution in GRF (or its N-acetylated derivative) by D-Phe2, D-Arg2, and D-Ala4 again reduced the intrinsic activity, whereas substitution of the natural L-amino acid residue by D-Ala2 and Phe4 gave superagonists.
Study Information
pubmed
1985
10.1210/endo-116-6-2643