Disease relevance of MC1R

• In contrast, variants of the melanocortin-1 receptor gene, MC1R, confer much lower melanoma risk but are common in European populations [1].
• This link between p16 and MC1R may provide a molecular basis for the increased skin cancer risk associated with MC1R polymorphisms [2].
• MC1R Arg(160)/Arg(160) homozygotes were at increased risk (P = 0.027, odds ratio = 1.94) while TYR A2/A2 homozygotes were at reduced risk of prostate cancer (P = 0.033, odds ratio = 0.48) [3].
• We examined MC1R and ASIP genotypes in relation to phenotypic characteristics, sporadic and familial melanoma risk, and melanoma thickness as an indicator of disease progression in a Mediterranean population [4].
• Also, the increased expression of MC1-R in subcutaneous fat of obese subjects may reflect one aspect of the pathophysiology of obesity [5].
• In addition to carrying MC1R variant alleles, having blond/red hair and childhood sunburns were independent risk factors for MM [6].

Psychiatry related information on MC1R

• This paper reviews the path of discovery of the MC1R in control of animal coat colour, the subsequent role of MC1R in human physiology and possibly wider role of MC1R in human skin carcinogenesis and human development through history [7].
• To study the possibility of disturbances in melanocortin receptor-related peptides in eating disorders, plasma AGRP, alpha-MSH, and leptin levels were measured in 18 female patients with anorexia nervosa (AN) (age, 23.5+/-7.1yr; body mass index (BMI) 14.5+/-1.8kg/m(2)) and 17 age-matched female controls (age, 25.8+/-3.9yr; BMI 20.2+/-1.6kg/m(2)) [8].
• In these studies, we measured changes in feeding behavior in ring doves (Streptopelia risoria) following intracerebroventricular (i.c.v.) injection of various melanocortin receptor agonists and antagonists [9].
• An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist [10].
• MB243 (a 1,3-disubstituted piperazine) is a new, potent, and selective melanocortin receptor subtype-4 agonist with potential application in the treatment of obesity and/or erectile dysfunction [11].

High impact information on MC1R

• The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortins and ACTH, whereas among the negative regulators agouti protein stands out, determining intensity of melanogenesis and also the type of melanin synthesized [12].
• Our findings suggest that in humans, as in other mammals, the MC1R is a control point in the regulation of pigmentation phenotype and, more importantly, that variations in this protein are associated with a poor tanning response [13].
• Preclinical investigations indicate that activation of certain MCR subtypes, primarily MC1R and MC3R, could be a novel strategy to control inflammatory disorders [14].
• Despite a large number of murine coat-color mutations, only one gene in humans, the melanocortin 1 receptor (MC1R), is known to account for substantial variation in skin and hair color and in skin cancer incidence [15].
• It remains to be investigated whether the interaction of MC1R and ASIP can enhance prediction of human pigmentation and melanoma risk [16].

Chemical compound and disease context of MC1R

• In overweight subjects, a decreased sensitivity to ACTH/MSH peptides may derive from alterations at the level of the melanocortin receptor or at subsequent steps in the processing of the body fat signal [17].
• Inhibition by melittin and fluphenazine of melanotropin receptor function and adenylate cyclase in M2R melanoma cell membranes [18].
• We review our experience with Melanotan II, a non-selective melanocortin receptor agonist, in human subjects with erectile dysfunction (ED) [19].
• Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and sildenafil to men with erectile dysfunction results in an enhanced erectile response [20].

Biological context of MC1R

• MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations [1].
• When an MC1R variant allele was also present, the raw penetrance of the CDKN2A mutation increased to 84%, with a mean age at onset of 37.8 years (P=.01) [1].
• Mutagenesis studies suggested that the targets of GRK6 are two residues located in the MC1R cytosolic C terminus, Thr-308 and Ser-316 [21].
• The human MC1R gene is highly polymorphic and certain allelic variants of the gene are associated with red hair phenotype, melanoma and non-melanoma skin cancer [22].
• Furthermore, three missense mutations (V92M) and two silent mutations (CGA (Arg) to CGG (Arg), codon 213, exon 6) were found in the MC1R and p53 genes, respectively [23].

Anatomical context of MC1R

• Herein, we define HLA-A2-restricted CTL epitopes from a recently cloned melanocortin 1 receptor (MC1R), which belongs to a new subfamily of the G-protein-coupled receptors expressed on melanomas and melanocytes [24].
• Melanocortin receptors (MC1R-MC5R) and their ligands (melanocyte-stimulating hormone (MSH) and adrenocorticotrophin hormone (ACTH)) have been shown to influence physiological functions of cells and organs, including exocrine glands [25].
• Their mechanisms of action cover (i) tyrosinase inhibition, maturation and enhancement of its degradation; (ii) Mitf inhibition; (iii) downregulation of MC1R activity; (iv) interference with melanosome maturation and transfer; (v) melanocyte loss, desquamation and chemical peeling [26].
• For this purpose, the effect of co-expression of cDNA encoding MITF on MC1R promoter activity in NIH/3T3 cells was studied [27].
• ACTH and alpha-MSH bind to MC1R to influence both pigmentation and the immune system [28].

Associations of MC1R with chemical compounds

• However, in the MC1R, these serine residues corresponded to Val(122), which contains two methyl groups that induce steric hindrance with D-Phe(7) of [Gln(6)]alpha-MSH-ND [29].
• To investigate whether residues in the extracellular domains of melanocortin 1 receptor (MC1R) are required for ligand binding, a number of mutants were constructed where charged residues were converted to alanine [30].
• These data demonstrate that the His-Phe-Arg-Trp message sequence of the melanocortin peptides does not bind and stimulate each melanocortin receptor in a similar fashion, as previously hypothesized [31].
• Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic approach [32].
• The dependence of agonist binding on the dithiothreitol concentration followed a monophasic curve for wild-type hMC4R and its C40A, C271A, and C279A mutants and a biphasic curve for hMC1R, suggesting the presence of at least one structurally and functionally essential disulfide bond in both wild-type receptors and the hMC4R mutants [33].
• The V92M variant cAMP activation was equal to or higher than that for wild-type MC1R [34].

Physical interactions of MC1R

• Although previous studies have shown that AGRP binds three of the five known subtypes of melanocortin receptor, the receptor domains participating in binding and the molecular interactions involved are presently unknown [35].
• We have shown that alpha-MSH and ACTH bind the human MC1R with equal affinity, and are equipotent in their mitogenic and melanogenic effects on human melanocytes [36].
• Moreover, TRH could be docked into a binding pocket of a molecular model of the MC1 receptor at only a little higher energy than a short cyclic MSH peptide [37].
• The C-terminal segment (Gly10-Lys11-Pro12-Val13) of NDP was clearly important for binding to all the four melanocortin receptor subtypes [38].
• Melanocortin hormones and neurotransmitters regulate a vast array of physiologic processes by interacting with five G-protein-coupled melanocortin receptor types [39].

Regulatory relationships of MC1R

• The extent and kinetics of Agrp-promoted MCR endocytosis were similar to the endocytosis induced by melanocortins [40].
• Penetrance of CDKN2A gene was found to be significantly influenced by host factors (nevus phenotypes and sunburn) on one hand and by variants of MC1R gene (RHC variants consistently associated with red hair and fair skin) on the other hand [41].
• We hypothesise that melanocortin receptor blockade attenuates a tonic influence of alpha-MSH on nociception, thus allowing the analgesic effects of beta-endorphin to develop, resulting in the alleviation of allodynia [42].
• This study addresses this problem by comparing tyrosinase stimulatory activity with their receptor binding affinity in B16 murine melanoma cells expressing the native MC1 melanocortin receptor [43].
• The ability to stimulate phosphorylation of the cAMP response element binding protein (CREB) transcription factor was also apparent in all stimulated MC1R variant allele-expressing HEK293 cell extracts as assessed by immunoblotting [44].

Other interactions of MC1R

• This report provides the details of the molecular recognition of SHU9119 antagonism at hMC4R and shows that amino acid Leu(133) of hMC4R plays a key role in melanocortin receptor subtype specificity [45].
• The structure also suggests that AGRP possesses an additional melanocortin-receptor contact region within a loop formed by the first 16 residues of its C-terminal domain [46].
• ACTH1-17 is a more potent agonist at the human MC1 receptor than alpha-MSH [47].
• MC1R was sequenced, ASIP was genotyped, and DNA repair capacity was measured by the host-cell reactivation assay [4].
• DISCUSSION: The expression of MC1-R and the lack of MC2-R in human adipose tissues indicate that the melanocortins may regulate cell proliferation and/or inflammatory signals rather than lipolysis [5].

Analytical, diagnostic and therapeutic context of MC1R

• In addition, electrophoretic mobility shift assay indicated that nuclear extracts of human SK-Mel-2 cells contain a protein that binds specifically to the MC1R promoter region containing the CATGTG motif [27].
• Molecular cloning of a novel human melanocortin receptor [48].
• Distribution of cDNA for five individual melanocortin receptor subtypes in 20 different human tissues was determined by PCR using subtype specific primers [49].
• We found that women with two variant MC1R alleles displayed significantly greater analgesia from the kappa-opioid, pentazocine, than all other groups [50].
• Using immunofluorescence and ligand binding studies, we found that melanocytic cells exogenously or endogenously expressing MC1R show strong surface localization of the wild-type and D294H alleles but markedly reduced cell surface expression of the R151C and R160W receptors [51].

References