The Role of Melanocortins in Skin Homeostasis

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Abstract

Melanocortins are structurally related bioactive peptides which are produced by many extra-neural tissues including the skin. All of the melanocortins (α, β, and γ-melanocyte-stimulating hormone and adrenocorticotropin) have melanotropic activity but can elicit many other effects on skin cells. On the basis of in vitro and in vivo findings melanocortins have been shown to regulate immune and inflammatory responses, hair growth, exocrine gland activity and extracellular matrix composition. These effects are mediated by melanocortin receptors among which the melanocortin-1 receptor is most ubiquitously expressed by human skin cells. Simultaneous expression of melanocortins and their receptors suggest a complex autocrine and/or paracrine regulatory network whose disruption invariably affects skin homeostasis. Expression of melanocortin receptors on various skin cell types further indicates novel pharmacological targets for the treatment of skin diseases.

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Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype?

D Duffy, R L O'Gorman, David R. J. Palmer … (1999)

Risk of cutaneous malignant melanoma (CMM) is increased in sun-exposed whites, particularly those with a pale complexion. This study was designed to investigate the relationship of the melanocortin-1 receptor (MC1R) genotype to CMM risk, controlled for pigmentation phenotype. We report the occurrence of five common MC1R variants in an Australian population-based sample of 460 individuals with familial and sporadic CMM and 399 control individuals-and their relationship to such other risk factors as skin, hair, and eye color; freckling; and nevus count. There was a strong relationship between MC1R variants and hair color and skin type. Moreover, MC1R variants were found in 72% of the individuals with CMM, whereas only 56% of the control individuals carried at least one variant (P<.001), a finding independent of strength of family history of melanoma. Three active alleles (Arg151Cys, Arg160Trp, and Asp294His), previously associated with red hair, doubled CMM risk for each additional allele carried (odds ratio 2.0; 95% confidence interval 1. 6-2.6). No such independent association could be demonstrated with the Val60Leu and Asp84Glu variants. Among pale-skinned individuals alone, this association between CMM and MC1R variants was absent, but it persisted among those reporting a medium or olive/dark complexion. We conclude that the effect that MC1R variant alleles have on CMM is partly mediated via determination of pigmentation phenotype and that these alleles may also negate the protection normally afforded by darker skin coloring in some members of this white population.

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Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA.

Vijay Chhajlani, Jarl E.S. Wikberg (1992)

Melanocytes and melanoma cells are known to possess receptors for melanocyte stimulating hormone (MSH). A cDNA clone, designated 11D, has been isolated from human melanoma cells and encodes a MSH receptor. The cloned cDNA encodes a 317 amino acid protein with transmembrane topography characteristics of a G-protein-coupled receptor, but it does not show striking similarity to already published sequences of other G-protein-coupled receptors. When 11D cDNA is expressed in COS-7 cells, it binds an 125I-labelled MSH analogue (NDP-MSH) in a specific manner. The bound ligand could be displaced by melanotropic peptides, alpha-MSH, beta-MSH, gamma-MSH and ACTH (adrenocorticotropic hormone), but not by the non-melanotropic peptide, beta-endorphin. This is the first report of the cloning of the receptor gene of the melanotropin receptor family.

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Melanocortin 1 receptor variants in an Irish population.

M Machin, I Rosdahl, I Jackson … (1998)

The identification of an association between variants in the human melanocortin 1 receptor (MC1R) gene and red hair and fair skin, as well as the relation between variants of this gene and coat color in animals, suggests that the MC1R is an integral control point in the normal pigmentation phenotype. In order to further define the contribution of MC1R variants to pigmentation in a normal population, we have looked for alterations in this gene in series of individuals from a general Irish population, in whom there is a preponderance of individuals with fair skin type. Seventy-five per cent contained a variant in the MC1R gene, with 30% containing two variants. The Arg151Cys, Arg160Trp, and Asp294His variants were significantly associated with red hair (p = 0.0015, p < 0.001, and p < 0.005, respectively). Importantly, no individuals harboring two of these three variants did not have red hair, although some red-haired individuals only showed one alteration. The same three variants were also over-represented in individuals with light skin type as assessed using a modified Fitzpatrick scale. Despite these associations many subjects with dark hair/darker skin type harbored MC1R variants, but there was no evidence of any particular association of variants with the darker phenotype. The Asp294His variant was similarly associated with red hair in a Dutch population, but was infrequent in red-headed subjects from Sweden. The Asp294His variant was also significantly associated with nonmelanoma skin cancer in a U.K. population. The results show that the Arg151Cys, Arg160Trp, and Asp294His variants are of key significance in determining the pigmentary phenotype and response to ultraviolet radiation, and suggest that in many cases the red-haired component and in some cases fair skin type are inherited as a Mendelian recessive.

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Author and article information

Journal

Journal ID (publisher-id): HRE

Journal ID (nlm-ta): Horm Res Paediatr

Journal ID (doi): 10.1159/issn.1663-2818

Title: Hormone Research in Paediatrics

Publisher: S. Karger AG

ISBN: 978-3-8055-7317-7

ISBN: 978-3-318-00781-7

ISSN (Print): 1663-2818

ISSN (Electronic): 1663-2826

Publication date Subscription-year: 2000

Publication date (Print): 2000

Publication date (Electronic): 28 September 2001

Volume: 54

Issue: 5-6

Pages: 287-293

Affiliations

Department of Dermatology and Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, University of Münster, Germany

Article

Publisher ID: 53273 Other ID: Horm Res 2000;54:287–293

DOI: 10.1159/000053273

PubMed ID: 11595819

SO-VID: 6a48dd07-20d9-4c40-95db-52f70b5e2be4

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The Role of Melanocortins in Skin Homeostasis

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Karger: Endocrinology

Most cited references 17

Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype?

Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA.

Melanocortin 1 receptor variants in an Irish population.

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