Disease relevance of Mc1r

• We found that the human melanocortin 1 receptor (MC1R) and its mouse ortholog (Mc1r) undergo homologous desensitization in melanoma cells [1].
• Moreover, spontaneous dominant mutations of the agouti gene in several strains of mice lead to its ubiquitous overexpression and produces not only yellow coat color, but also obesity and insulin resistance, perhaps as a result of its antagonism of other MCR subtypes [2].
• Crucial role of the melanocortin receptor MC1R in experimental colitis [3].
• In young nonobese animals, melanocortin receptor blockade associated with the Ay mutation causes complete resistance to leptin-induced weight loss [4].
• The first of these to be cloned, agouti, antagonizes central nervous system melanocortin receptor (MCR) binding, resulting in hyperphagia and an obesity/hyperinsulinemia syndrome [5].

High impact information on Mc1r

• In the mouse, extension is epistatic to agouti, hence dominant mutants of the MC1R encoding constitutively active receptors are not inhibited by the agouti antagonist, and animals with dominant alleles of both loci remain darkly pigmented [6].
• A constitutively activating C125R mutation in the MC1R was found specifically in darkly pigmented animals carrying the Alaska Silver allele (EA) [6].
• These observations provide new insight into the regulation of energy metabolism and indicate a molecular basis for crosstalk between melanocortin-receptor signalling and immune function [7].
• Bone morphogenetic protein (BMP) signaling controls hair pigmentation by means of cross-talk with the melanocortin receptor-1 pathway [8].
• Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor (Mc1r) gene mediates kappa-opioid analgesia in female mice only [9].

Chemical compound and disease context of Mc1r

• These results indicate that the labeled 45-kDa glycoprotein contains terminal sialic acid residues, explaining the low pI of this protein, and that it is characteristic for melanoma cells and hence part of the MSH receptor [10].
• Also, in contrast to leptin, cerulenin was highly effective to reduce body weight in Ay mice, in which obesity is caused by blockade of the melanocortin receptor [11].
• Calmodulin-binding peptides interfere with melanocyte-stimulating hormone receptor activity and stimulate adenosine 3',5'-monophosphate production in M2R mouse melanoma cells [12].

Biological context of Mc1r

• In 293T cells, expression of the Mc1r confers a specific, high-affinity binding site for HA-Agouti [13].
• We show that a mouse bacterial artificial chromosome (BAC) which contains Mc1r will efficiently rescue loss of Mc1r in transgenic mice, and that overexpression of the receptor suppresses the effect of the endogenous antagonist, agouti protein [14].
• We examined the influence of ASP or MSH on Mc1r gene expression, and we report that both ligands influence the Mc1r 5' promoter structure in distinct manners [15].
• For this reason alanine-scanning mutagenesis was performed on the agouti protein carboxyl terminus to locate residues important for melanocortin receptor binding inhibition [16].
• Agouti was also found to induce MC1-R down-regulation with identical kinetics and magnitude as alpha-MSH [17].

Anatomical context of Mc1r

• These effects provide an explanation for the interactions in mice of melanocyte developmental mutations with yellow agouti and Mc1r alleles, and a role for embryonic expression patterns of ASP [18].
• Alpha-melanocyte-stimulating hormone suppresses antigen-induced lymphocyte proliferation in humans independently of melanocortin 1 receptor gene status [19].
• By contrast, the expression of the MC1-R gene in the dermis was first observed in 16 d old embryos, and gradually increased up to 3.5 d after birth, and thereafter remained constant [20].
• MCR are also found in melanocytic cells and adrenal cortical cells, the classical targets for alpha-MSH and ACTH, respectively, in myelogenous and lymphoid tissues, and in various endocrine and exocrine glands, adipocytes, and in autonomic ganglia [2].
• The melanocortin 3 receptor (MC3-R) in the melanocortin receptor family has been identified as a neural receptor subtype mainly expressed in the brain in mammals [21].

Associations of Mc1r with chemical compounds

• The endogenous melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp," postulated to be important for melanocortin receptor molecular recognition and stimulation [22].
• Additionally, these studies identified that substitution of the Trp amino acid with either Nal(2') or D-Nal(2') resulted in equipotent melanocortin receptor potency, suggesting that the chemically reactive Trp indole side chain may be replaced with the nonreactive Nal(2') moiety for the design of nonpeptide melanocortin receptor agonists [22].
• Here we demonstrate that topical application of dexamethasone during anagen VI decreased the concentration of POMC, MC1-R, and tyrosinase mRNA in the skin [23].
• Effects of melanocortin receptor activation and blockade on ethanol intake: a possible role for the melanocortin-4 receptor [24].
• Human dermal fibroblasts in vitro express a high affinity binding site for MSH, which was identified by reverse transcription PCR and immunofluorescence analysis as the melanocortin-1 receptor (MC-1R) [25].

Physical interactions of Mc1r

• AGRP binds as an endogenous antagonist or inverse agonist of the central melanocortin receptors but has also been hypothesized to have melanocortin receptor-independent effects [26].
• Melanocortin receptor binding determinants in the agouti protein [16].
• New Melanocortin 1 Receptor Binding Motif Based on the C-Terminal Sequence of alpha-Melanocyte-Stimulating Hormone [27].

Regulatory relationships of Mc1r

• The anti-inflammatory properties of KPV were also evident in IL-1beta-induced peritonitis inflammation and in mice with a nonfunctional MC1-R (recessive yellow e/e mice) [28].
• A selective small molecule agonist of the melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice [29].

Other interactions of Mc1r

• Here we have addressed this aspect using a dual pharmacological and genetic approach, taking advantage of the recent characterization of more selective agonists/antagonists at MC1 and MC3-R as well as of the existence of a naturally defective MC1-R mouse strain, the recessive yellow (e/e) mouse [30].
• These results support the hypothesis that murine hair growth and attendant melanogenesis can be regulated through coordinated changes in local expression of POMC, MC1-R, and tyrosinase genes [23].
• Novel agouti-related-protein-based melanocortin-1 receptor antagonist [31].
• These results suggest that the expression of the MC1-R gene, but not of the POMC gene, plays an important role in the regulation of melanocyte differentiation in mouse skin [20].
• An MSH binding site characterized in these cells is presumably the MC5 receptor, based on the observation that this is the only other melanocortin receptor mRNA detected in these cells [32].

Analytical, diagnostic and therapeutic context of Mc1r

• An allelism test indicated the tawny mutant gene to be a new allele at the Mc1r locus and dominant to the recessive yellow (Mc1re) [33].
• Molecular cloning, expression, and characterization of a fifth melanocortin receptor [34].
• MC1Re/e mice receiving MC1R+ bone marrow showed a similar course of inflammation to non-transplanted MC1Re/e. Likewise, transplantation of MC1R bone marrow into C57BL/6WT mice did not lead to any worsening of disease [3].
• Semiquantitative RT-PCR demonstrated that monocytes and DC express MC-1R, but none of the other members of the MC-receptor family [35].
• To better understand how Mc1r signaling affects different cutaneous phenotypes, we examined large-scale patterns of gene expression in different skin components (whole epidermal sheets, basal epidermal cells and whole skins) of neonatal (P2.5) normal and recessive yellow mice, starting with a 26K mouse cDNA microarray [36].

References