Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo
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Agouti protein and Agouti-related protein (Agrp) are paracrine-signaling molecules that normally regulate pigmentation and body weight, respectively. These proteins antagonize the effects of alpha-melanocyte-stimulating hormone (alpha-MSH) and other melanocortins, and several alternatives have been proposed to explain their biochemical mechanisms of action. We have used a sensitive bioassay based on Xenopus melanophores to characterize pharmacologic properties of recombinant Agouti protein, and have directly measured its cell-surface binding to mammalian cells by use of an epitope-tagged form (HA-Agouti) that retains biologic activity. In melanophores, Agouti protein has no effect in the absence of alpha-MSH, but its action cannot be explained solely by inhibition of alpha-MSH binding. In 293T cells, expression of the Mc1r confers a specific, high-affinity binding site for HA-Agouti. Binding is inhibited by alpha-MSH, or by Agrp, which indicates that alpha-MSH and Agouti protein bind in a mutually exclusive way to the Mc1r, and that the similarity between Agouti protein and Agrp includes their binding sites. The effects of Agouti and the Mc1r in vivo have been examined in a sensitized background provided by the chinchilla (Tyrc-ch) mutation, which uncovers a phenotypic difference between overexpression of Agouti in lethal yellow (Ay/a) mice and loss of Mc1r function in recessive yellow (Mc1re/Mc1re) mice. Double and triple mutant studies indicate that a functional Mc1r is required for the pigmentary effects of Agouti, and suggest that Agouti protein can act as an agonist of the Mc1r in a way that differs from alpha-MSH stimulation. These results resolve questions regarding the biochemical mechanism of Agouti protein action, and provide evidence of a novel signaling mechanism whereby alpha-MSH and Agouti protein or Agrp function as independent ligands that inhibit each other's binding and transduce opposite signals through a single receptor.
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Asip1 and the orthologous protein of mammals, Asip, are Melanocortin-1 receptor (Mc1r) antagonists and their ventral expression inhibits differentiation of melanophores and melanocytes, respectively, resulting in light bellies.
“Asip1 and the orthologous protein of mammals, Asip, are Melanocortin-1 receptor (Mc1r) antagonists and their ventral expression inhibits differentiation of melanophores and melanocytes, respectively, resulting in light bellies (24–27).”
From Agouti and BMP signaling drive a naturally occurring fate conversion of melanophores to leucophores in zebrafish (2025) · cites this paper as [24]
The Discussion (page unavailable) states that Agouti antagonizes Mc1r, and the paper describes Agouti shifting pigment production in mammalian melanocytes toward yellow. It does not establish that Agouti inhibits melanocyte differentiation or that ventral expression produces light bellies. The Concluding remarks (page unavailable) treat an Agouti homolog involved in amphibian dorsal–ventral pigmentation as speculative; the paper does not establish the claim about Asip1 in fish. (LLM, conf=0.89)
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- Authors
- Ollmann, M. M., Lamoreux, M. L., Wilson, B. D., & Barsh, G. S.
- Affiliations
- Howard Hughes Medical Institute (US)
- ORCID
- Barsh, G. S.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1998-02-01
- Volume
- 12
- Issue
- 3
- Pages
- 316-330
- ISSN
- 0890-9369 (ISSN-L)
- PMC
- PMC316484
- OpenAlex
- W2106052620
- Cited by
- 226
- References
- 0
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 10 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 8 · 2017: 6 · 2016: 7 · 2015: 4 · 2014: 20 · 2013: 6 · 2012: 4
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Eye Institute (EY 07106, EY-10223, T32EY007106, R01EY010223)
- National Institute of General Medical Sciences (T32GM007365, GM 07365)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- agouti protein, MC1R, agouti-related protein, alpha-melanocyte-stimulating hormone, receptor antagonism, receptor binding, melanophores, pigmentation, body weight regulation, receptor agonism, signaling mechanisms
- MeSH terms
- alpha-MSH, Animals, Epitopes, Melanophores, Mice, Inbred C57BL, Pigmentation, Protein Binding, Proteins, Recombinant Proteins, Xenopus, Receptors, Corticotropin, Intercellular Signaling Peptides and Proteins, Receptors, Melanocortin, Mice, Agouti Signaling Protein, Agouti-Related Protein
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