Agouti-related protein (83-132) is a competitive antagonist at the human melanocortin-4 receptor: no evidence for differential interactions with pro-opiomelanocortin-derived ligands.
Pritchard. L E LE; Armstrong. D D; Davies. N N; Oliver. R L RL; Schmitz. C A CA; Brennand. J C JC; Wilkinson. G F GF; White. A A
Key Findings
- AGRP (83‑132) acts as a competitive (orthosteric) antagonist at the MC4‑R, not an allosteric modulator.
- Various POMC‑derived peptides (α‑MSH, β‑MSH, da‑α‑MSH, ACTH, etc.) have similar affinity and potency at MC4‑R.
- Blocking MC4‑R with AGRP does not change how quickly a labeled MSH analogue leaves the receptor, supporting the competitive antagonism model.
Practical Outcomes
- For most biohackers, this work doesn’t change how you would use melanotan‑I or similar peptides, because it focuses on a different molecule (AGRP) that blocks the same receptor rather than activates it. It confirms that MC4‑R can be modulated by multiple natural hormones, but offers no new dosing guidance or safety data for self‑experimentation.
Summary
The study shows that a fragment of the protein agouti‑related protein (AGRP 83‑132) blocks the human melanocortin‑4 receptor (MC4‑R) in a straightforward, competitive way, without any fancy allosteric tricks. It also finds that many natural hormones derived from POMC, like different forms of melanocyte‑stimulating hormone, bind the same receptor with similar strength, meaning they could all play a role in controlling appetite.
Abstract
Interactions between pro-opiomelanocortin (POMC)-derived peptides, agouti-related protein (AGRP) and the melanocortin-4 receptor (MC4-R) are central to energy homeostasis. In this study we have undertaken comprehensive pharmacological analysis of these interactions using a CHOK1 cell line stably transfected with human MC4-R. Our main objectives were (1) to compare the relative affinities and potencies of POMC-derived peptides endogenously secreted within the hypothalamus, (2) to investigate the potency of AGRP(83-132) antagonism with respect to each POMC-derived peptide and (3) to determine whether AGRP(83-132) and POMC-derived peptides act allosterically or orthosterically. We have found that beta melanocyte-stimulating hormone (betaMSH), desacetyl alpha MSH (da-alphaMSH) and adrenocorticotrophic hormone all have very similar affinities and potencies at the MC4-R compared with the presumed natural ligand, alphaMSH. Moreover, even MSH precursors, such as beta lipotrophic hormone, showed significant binding and functional activity. Therefore, many POMC-derived peptides could have important roles in appetite regulation and it seems unlikely that alphaMSH is the sole physiological ligand. We have shown that AGRP(83-132) acts as a competitive antagonist. There was no significant difference in the potency of inhibition by AGRP(83-132) or agouti(87-132) at the MC4-R, regardless of which POMC peptide was used as an agonist. Furthermore, we have found that AGRP(83-132) has no effect on the dissociation kinetics of radiolabelled Nle4,D-Phe7 MSH from the MC4-R, indicating an absence of allosteric effects. This provides strong pharmacological evidence that AGRP(83-132) acts orthosterically at the MC4-R to inhibit Gs-coupled accumulation of intracellular cAMP.
Study Information
pubmed
2004
10.1677/joe.0.1800183