Pharmacological Characterization of Loss of Function Mutations of the Human Melanocortin 1 Receptor That Are Associated with Red Hair

Ringholm, Aneta; Kloviņš, Jānis; Rudzish, Richard; Phillips, Siôn R.; Rees, Jonathan; Schiöth, Helgi B.

doi:10.1111/j.0022-202x.2004.23444.x

Cited by 104 publications

(108 citation statements)

References 30 publications

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“…It is more plausible that the decrease in basal activity reflects a polymorphism-induced transition to a less active receptor state with an accompanying decrease in agonist potency as predicted by the extended ternary model (Lefkowitz et al, 1993). The V60L and R163Q polymorphisms displayed agonist potency and affinity similar to the wild-type receptor, consistent with previous reports (Schiöth et al, 1995;Ringholm et al, 2004;Beaumont et al, 2005Beaumont et al, , 2007.…”

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confidence: 87%

Selected Melanocortin 1 Receptor Single-Nucleotide Polymorphisms Differentially Alter Multiple Signaling Pathways

Doyle¹,

Fortin²,

Beinborn³

et al. 2012

J Pharmacol Exp Ther

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The melanocortin 1 receptor (MC1R) is a highly polymorphic G protein-coupled receptor, which is known to modulate pigmentation and inflammation. In the current study, we investigated the pharmacological effects of select single-nucleotide polymorphisms (SNPs) (V60L, R163Q, and F196L). After transient expression of MC1Rs in human embryonic kidney 293 cells, basal and ligand-induced cAMP signaling and mitogen-activated protein kinase (MAPK) activation were assessed by using luciferase reporter gene assays and Western blot analysis, respectively. All receptor variants showed decreased basal cAMP activity. With the V60L and F196L variants, the decrease in constitutive activity was attributable, at least in part, to a reduction in surface expression. The F196L variant also displayed a significant reduction in potency for both the peptide agonist ␣-melanocyte-stimulating hormone (␣-MSH) and the small-molecule agonist 1-[1-(3-methyl-L-histidyl-O-methyl-Dtyrosyl)-4-phenyl-4-piperidinyl]-1-butanone (BMS-470539). In MAPK signaling assays, the F196L variant showed decreased phospho-extracellular signal-regulated kinase levels after stimulation with either ␣-MSH or BMS-470539. In contrast, the R163Q variant displayed a selective loss of ␣-MSH-induced MAPK activation; whereas responsiveness to the small-molecule agonist BMS-470539 was preserved. Further assessment of MC1R variants in A549 cells, an in vitro model of inflammation, revealed an enhanced inflammatory response resulting from expression of the F196L variant (versus the wild-type MC1R). This alteration in function was restored by treatment with BMS-470539. Overall, these studies illustrate novel signaling profiles linked to distinct MC1R SNPs. Furthermore, our investigations highlight the potential for small-molecule drugs to rescue the function of MC1R variants that show reduced basal and/or ␣-MSH stimulated activity.

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confidence: 87%

Selected Melanocortin 1 Receptor Single-Nucleotide Polymorphisms Differentially Alter Multiple Signaling Pathways

Doyle¹,

Fortin²,

Beinborn³

et al. 2012

J Pharmacol Exp Ther

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“…The R163Q variant in earlier studies was associated with lower affinity for a-MSH but normal level of cAMP response than wild type MC1R. 31 However, more recent studies have associated this variant with decreased surface expression, reduced affinity for a-MSH as well as cAMP signaling but to a lower extent than the RHC alleles. 30,33 Nonpigmentary functions of MC1R include regulation of cytokines and their receptors involved in immune and inflammatory responses through modulation of NF-jB.…”

Section: Discussionmentioning

confidence: 93%

MC1R variants associated susceptibility to basal cell carcinoma of skin: Interaction with host factors and XRCC3 polymorphism

Scherer

Bermejo

Rudnai

et al. 2007

Intl Journal of Cancer

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The variants within the human melanocortin 1 receptor (MC1R) gene are associated with an increased risk of different skin cancers. In this study, we genotyped by direct sequencing, 529 cases of basal cell carcinoma of the skin (BCC) and 533 healthy controls for polymorphisms in the entire MC1R gene. In addition to 10 common polymorphisms, we detected 23 rare variants in the gene. The presence of any nonsynonymous MC1R variant was associated with an increased risk in the carriers (odds ratio OR 1.66, 95% confidence interval CI 1.28-2.14) corresponding to a population attributable fraction of about 27%. The odds ratio for the risk in the carriers of 2 MC1R variants was 2.69 (95% CI 1.77-4.08). The risk of BCC in the carriers of MC1R variants with fair complexion was almost twice as much as in the corresponding noncarriers. The carriers of the R163Q variant with a medium skin complexion were at a 3-fold higher risk than the noncarrier counterparts. The interaction, of effect on the BCC risk, between the MC1R variants and types of skin response to sun exposure was greater than multiplicative. We also observed a multiplicative interaction of risk due to the MC1R variants and the common allele (high risk) of the T241M polymorphism in the XRCC3 gene. Our data confirmed the status of the nonsynonymous MC1R variants as independent genetic risk factors for BCC. However, the mechanism through which the variants influence the risk likely involves complex interactions with other genetic and host risk factors. ' 2007 Wiley-Liss, Inc.Key words: MC1R; polymorphisms; basal cell carcinoma; complexion; interactions Skin pigmentation and DNA repair constitute intrinsic mechanisms evolved to prevent skin carcinogenesis. 1,2 Skin pigmentation, which inhibits DNA damage, manifests a preventive and DNA repair a corrective mechanism. A number of genes involved both in DNA repair and pigmentation, contingent to environmental and other historical selection constraints, are highly polymorphic. [3][4][5] Many of the polymorphisms in the genes involved in these processes, as a corollary, modulate the risk and contribute to the inter-individual differences in susceptibility to the skin cancers including basal cell carcinoma of skin (BCC). [6][7][8][9] The G-protein coupled Melanocortin receptor 1 (MC1R) is a pivotal component in the pathway involved in the production of melanin in melanocytes. 10 Activation of MC1R by a-MSH (a-melanocyte-stimulating hormone) leads to increased cellular cAMP. The levels of cAMP, through tyrosinase, control the switch over of synthesis from pheomelanin to photo protective eumelanin. 11 The gene encoding MC1R is highly polymorphic and many variants are associated with an increased risk of skin cancers. 12,13 More than 60 nonconservative variants of the receptor are known and at least 3 frequent variants are strongly associated with high risk phenotypes of red hair and fair skin (RHC alleles; R151C, R160W and D294H) in Caucasians. [14][15][16] Several studies have reported association between variants in the MC1R...

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“…MC1R preferentially binds the pro-opiomelanocortin-derived peptides ␣-melanocyte-stimulating hormone (␣-MSH) and adrenocorticotropic hormone, which leads to an elevation in intracellular cAMP levels (10). RHC variant MC1Rs have been demonstrated to elicit weak cAMP responses as a result of reduced receptor coupling (2,(11)(12)(13) or abnormal receptor localization (2,(12)(13)(14)(15). Molecular analysis has revealed that MC1R signaling modulates the expression and function of the microphthalmia-associated transcription factor, a key regulator of pigmentation genes, suggesting that this pathway underlies MC1R coordination of melanogenesis (16).…”

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confidence: 99%

Melanocortin-1 Receptor Signaling Markedly Induces the Expression of the NR4A Nuclear Receptor Subgroup in Melanocytic Cells

Smith¹,

Luk²,

Newton

et al. 2008

Journal of Biological Chemistry

107

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The melanocortin-1 receptor (MCIR) is a G-protein-coupled receptor expressed primarily in melanocytes and is known to play a pivotal role in the regulation of pigmentation in mammals. In humans MC1R has been found to be highly polymorphic with several functional variants associated with the phenotype of red hair color and fair skin, cutaneous UV sensitivity, and increased risk of developing melanoma and non-melanoma skin cancer. Recent evidence suggests that MC1R plays a photo-protective role in melanocytes in response to UV irradiation. Relatively few genetic targets of MC1R signaling have been identified independent of the pigmentation pathway. Here we show that MC1R signaling in B16 mouse melanoma cells and primary human melanocytes rapidly, and transiently, induces the transcription of the NR4A subfamily of orphan nuclear receptors. Furthermore, primary human melanocytes harboring homozygous RHC variant MC1R alleles exhibited an impaired induction of NR4A genes in response to the potent MC1R agonist (Nle4,D-Phe7)-␣-melanocyte-stimulating hormone. Using small interference RNA-mediated attenuation of NR4A1 and NR4A2 expression in melanocytes, the ability to remove cyclobutane pyrimidine dimers following UV irradiation appeared to be impaired in the context of MC1R signaling. These data identify the NR4A receptor family as potential mediators of an MC1R-coordinated DNA damage response to UV exposure in melanocytic cells.It has long been recognized that individuals with fair skin and poor tanning ability have an increased incidence of melanoma and non-melanoma skin cancer (1-3). Cutaneous pigmentation in humans is the result of melanin synthesis by epidermal melanocytes within specialized organelles termed melanosomes, which are transferred to surrounding keratinocytes (4).Human pigmentation is a polygenic trait with Ͼ60 genetic loci identified so far (5, 6). Efforts over the last decade to understand the genetic basis of human pigmentary traits have revealed the melanocortin-1 receptor (MC1R) 5 as a key determinant of the wide phenotypic diversity in mammals (7-9). MC1R is a seven-transmembrane G-protein-coupled receptor that has been found to be highly polymorphic in Caucasian individuals, with a number of functional variants strongly associating with a phenotype of red hair, fair skin, and poor tanning ability often referred to as the Red Hair Color (RHC) phenotype (7). MC1R preferentially binds the pro-opiomelanocortin-derived peptides ␣-melanocyte-stimulating hormone (␣-MSH) and adrenocorticotropic hormone, which leads to an elevation in intracellular cAMP levels (10). RHC variant MC1Rs have been demonstrated to elicit weak cAMP responses as a result of reduced receptor coupling (2, 11-13) or abnormal receptor localization (2, 12-15). Molecular analysis has revealed that MC1R signaling modulates the expression and function of the microphthalmia-associated transcription factor, a key regulator of pigmentation genes, suggesting that this pathway underlies MC1R coordination of melanogenesis (16). Accumulating ...

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Pharmacological Characterization of Loss of Function Mutations of the Human Melanocortin 1 Receptor That Are Associated with Red Hair

Cited by 104 publications

References 30 publications

Selected Melanocortin 1 Receptor Single-Nucleotide Polymorphisms Differentially Alter Multiple Signaling Pathways

Selected Melanocortin 1 Receptor Single-Nucleotide Polymorphisms Differentially Alter Multiple Signaling Pathways

MC1R variants associated susceptibility to basal cell carcinoma of skin: Interaction with host factors and XRCC3 polymorphism

Melanocortin-1 Receptor Signaling Markedly Induces the Expression of the NR4A Nuclear Receptor Subgroup in Melanocytic Cells

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