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

L. E. Pritchard, d. Armstrong, N. Davies, R. L. Oliver, C. A. Schmitz, J. C. Brennand, G. F. Wilkinson, A. White

    Research output: Contribution to journalArticlepeer-review

    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 (βMSH), desacetyl alpha MSH (da-αMSH) and adreno-corticotrophic hormone all have very similar affinities and potencies at the MC4-R compared with the presumed natural ligand, αMSH. 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 αMSH 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.
    Original languageEnglish
    Pages (from-to)183-191
    Number of pages8
    JournalJournal of Endocrinology
    Volume180
    Issue number1
    DOIs
    Publication statusPublished - Jan 2004

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