The Melanocortin-2 Receptor in Normal Adrenocortical Function and Familial Adrenocorticotropic Hormone Resistance
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The physiologic role of adrenocorticotropic hormone (ACTH) and its part in the pituitary—adrenal axis is one of the most intensively studied systems in endocrinology. ACTH was one of the first hormones that was found to stimulate cAMP production by the adrenal gland (1), and the notion that this effect was mediated via a specific cell surface receptor was confirmed by the elegant studies of Lefkowitz and colleagues (2) in work that set a standard for receptor characterization. Nevertheless, progress on the understanding of the ACTH receptor has been relatively slow. It is now clear that the MC2-R is synonymous with the ACTH receptor, and both terms are used in this chapter. In general, the term ACTH receptor is used to describe the functional entity for example, ligand binding to adrenal cells, whereas the term MC2-R is used to describe aspects that can clearly be related to this gene.Keywords:
ACTH receptor
The physiologic role of adrenocorticotropic hormone (ACTH) and its part in the pituitary—adrenal axis is one of the most intensively studied systems in endocrinology. ACTH was one of the first hormones that was found to stimulate cAMP production by the adrenal gland (1), and the notion that this effect was mediated via a specific cell surface receptor was confirmed by the elegant studies of Lefkowitz and colleagues (2) in work that set a standard for receptor characterization. Nevertheless, progress on the understanding of the ACTH receptor has been relatively slow. It is now clear that the MC2-R is synonymous with the ACTH receptor, and both terms are used in this chapter. In general, the term ACTH receptor is used to describe the functional entity for example, ligand binding to adrenal cells, whereas the term MC2-R is used to describe aspects that can clearly be related to this gene.
ACTH receptor
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Objective To explore the possible correlation between the genetic variations of the melanocortin receptors (MCRs, including MC2R, MC3R and MC4R) and adrenocorticotropic hormone (ACTH) responsiveness in patients with infantile spasms, and to investigate the function of single nucleotide polymorphism (SNP) found in this study. Methods Direct sequencing method was used to test variations and polymorphisms in the promoter and coding regions of the MC2R, MC3R and MC4R gene. Haplotypes were structured by using SHEsis and Haploview3.32 programs to analyze the distribution frequencies of polymorphism genotypes, alleles and structured haplotypes in Chinese patients with infantile spasms and normal controls. The association between ACTH responsiveness and genetic variations was also assessed. Results Four SNPs were identified in the MC2R promoter region, one of which was new ⁃found locus named ⁃ 2T > C. Three SNPs (rs1893220, rs2186944 and ⁃ 2T > C) showed a significant difference between the cases and controls (P = 0.04, 0.02, 0.01). The common haplotype TCCT may give protection against the development of infantile spasms (P = 0.00). Besides, TCCT carriers were more sensitive to ACTH therapy than non⁃carriers (P = 0.00). The in vitro study proved that the translational efficiency of TCCT promoter in MC2R gene was four times higher than that of TCCC promoter (P = 0.00). MC2R expression assay showed a 5⁃fold increase in the TCCT promoter in presence of ACTH, compared with that in absence of ACTH (P = 0.00). However, responsiveness to ACTH in expression by TCCC promoter showed only 1.50⁃fold increase after ACTH stimulation (P > 0.05). The SNP rs11872992 in MC4R gene was related to the development of infantile spasms, as the efficiency of TC genotype in cases was lower than that of normal controls (P = 0.00). The ACTH therapy results of T⁃allele⁃carriers were better than that of non⁃T⁃allele⁃carriers (P = 0.01). The difference of SNP distribution frequencies in MC3R gene was not statistically significant (P > 0.05). Conclusion The study revealed an association between polymorphism in MCRs (MC2R and MC4R) promoter and the development of infantile spasms, and ACTH responsiveness in patients with infantile spasms. These findings may provide a clue for clinicians to find an early predictive marker for the responsiveness to ACTH and improve the understanding of pathogenesis in infantile spasms.
DOI：10.3969/j.issn.1672⁃6731.2012.05.012
ACTH receptor
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Crude membranes (20,000 x g pellet) prepared from human, rat, and ovine adrenals bind 1251-corticotropin-(l-24)tetracosapeptide (rz51-ACTH1-& and degrade unbound hormone.The degradation is dependent on temperature and the concentration of membrane proteins.The degradation of 1251-[9-tryptophan(o-nitrophenylsulfenyl)] -corticotropin -(1 -24) -tetracosapeptide (rz51 -NPS -ACTHI-21) is similar to 1251-ACTH1-24, but that of 1251-corticotropin-(11-24)-tetradecapeptide (1251-ACTH11-24) is larger.The degradation of 1251-ACTH1-24 is inhibited by ACTH1-24 and corticotropin-( 1 -IO)-decapeptide (ACTH&, but ACTHll-z4 at the same molar concentration has no effect.On the other hand, the degradation of 1251-ACTH11W2, is protected by ACTHll-24 and ACTHI-24, but not by ACTHlmlO.This suggests two systems of degradation, one will have the NH2-terminal sequence of ACTH,-2, as substrate, and the other the 11-24 COOH-terminal sequence.The main labeled product from the degradation of the 1251-ACTH1-24 and 1251-ACTH11-2, behaves as [1251]monoiodotyrosine on Sephadex G-50 and paper chromatography.The independence of ACTH binding to its receptor and degradation is demonstrated by the following facts.(a) Calcium and pancreatic trypsin inhibitor completely inhibit the binding at concentrations when the degradation is not altered; (b) the sequences of peptides of ACTH which inhibit the binding and degradation of 1251-ACTH,.24 are different.
ACTH receptor
Corticotropic cell
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Melanocortin 3 receptor
ACTH receptor
Melanocortin 1 receptor
Melanocortin 4 receptor
Melanocyte-stimulating hormone
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Melanocortin 4 receptor (MC4R), a canonical melanocyte-stimulating hormone receptor, is the main responsible for monogenic obesity in humans. Previous studies in fish and avian species showed that MC4R becomes an ACTH receptor after interaction with the melanocortin receptor accessory protein 2 (MRAP2). We show that human MC4R behaves in a similar way through its interaction with MRAP2. This evolutionary conservation of MRAP2-induced ligand selectivity supports a physiological role for the interaction with MC4R. Both proteins are coexpressed in the same hypothalamic neurons, providing an anatomical substrate and molecular mechanism for the central therapeutic actions of ACTH in the treatment of infantile spasms. These neurons may link the effects of stress on the energy balance independently of glucocorticoid secretion. The complex MC4R-MRAP2 throws light on the action of ACTH and, by extension, on the relay of stress-related information to additional biological systems.
ACTH receptor
Melanocortin 3 receptor
Melanocortin 4 receptor
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The ACTH receptor, known as the melanocortin-2 receptor (MC2R), plays an important role in regulating and maintaining adrenocortical function. MC2R is a subtype of the melanocortin receptor (MCR) family and has unique characteristics among MCRs. Endogenous ACTH is the only endogenous agonist for MC2R, whereas the melanocortin peptides α-, β-, and γ-melanocyte-stimulating hormone and ACTH are full agonists for all other MCRs. In this study, we examined the molecular basis of MC2R responsible for ligand selectivity using ACTH analogs and MC2R mutagenesis. Our results indicate that substitution of Phe7 with d-Phe or d-naphthylalanine (d-Nal(2′)) in ACTH(1–24) caused a significant decrease in ligand binding affinity and potency. Substitution of Phe7 with d-Nal(2′) in ACTH(1–24) did not switch the ligand from agonist to antagonist at MC2R, which was observed in MC3R and MC4R. Substitution of Phe7 with d-Phe7 in ACTH(1–17) resulted in the loss of ligand binding and activity. Molecular analysis of MC2R indicated that only mutation of the third transmembrane domain of MC2R resulted in a decrease in d-Phe ACTH binding affinity and potency. Our results suggest that Phe7 in ACTH plays an important role in ligand selectivity and that the third transmembrane domain of MC2R is crucial for ACTH selectivity and potency. The ACTH receptor, known as the melanocortin-2 receptor (MC2R), plays an important role in regulating and maintaining adrenocortical function. MC2R is a subtype of the melanocortin receptor (MCR) family and has unique characteristics among MCRs. Endogenous ACTH is the only endogenous agonist for MC2R, whereas the melanocortin peptides α-, β-, and γ-melanocyte-stimulating hormone and ACTH are full agonists for all other MCRs. In this study, we examined the molecular basis of MC2R responsible for ligand selectivity using ACTH analogs and MC2R mutagenesis. Our results indicate that substitution of Phe7 with d-Phe or d-naphthylalanine (d-Nal(2′)) in ACTH(1–24) caused a significant decrease in ligand binding affinity and potency. Substitution of Phe7 with d-Nal(2′) in ACTH(1–24) did not switch the ligand from agonist to antagonist at MC2R, which was observed in MC3R and MC4R. Substitution of Phe7 with d-Phe7 in ACTH(1–17) resulted in the loss of ligand binding and activity. Molecular analysis of MC2R indicated that only mutation of the third transmembrane domain of MC2R resulted in a decrease in d-Phe ACTH binding affinity and potency. Our results suggest that Phe7 in ACTH plays an important role in ligand selectivity and that the third transmembrane domain of MC2R is crucial for ACTH selectivity and potency.
ACTH receptor
Melanocortin 3 receptor
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The presence of specific cell surface receptors for adrenocorticotropic hormone (ACTH) was first demonstrated in 1970. However, characterization and localization of the ACTH binding site have been extensively studied in adrenal cells of different species only in the 1980s. Cloning of the human ACTH and α-MSH receptors in 1992 defined a new class of G protein coupled receptors: the melanocortin receptor family, which comprises five members named MC1-R to MC5-R where MC2-R is the ACTH receptor. Thereafter, characterization of the promoter of MC2-R gene revealed that the orphan nuclear receptor steroidogenic factor 1 (SF-1) is involved in the regulation of its activity like some other genes of the steroidogenic pathway. Several inactivating mutations in the MC2-R gene are responsible for the ACTH resistance found in the familial isolated glucocorticoid deficiency syndrome or FGD.
ACTH receptor
Cloning (programming)
Melanocortin 3 receptor
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ACTH receptor
Melanocortin 3 receptor
Melanocortin 4 receptor
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Melanocortin 3 receptor
ACTH receptor
Melanocortin 1 receptor
Melanocyte-stimulating hormone
Melanocortins
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ACTH receptor
Melanocortin 3 receptor
Melanocortin 1 receptor
Melanocortins
Melanocortin 4 receptor
Steroid hormone
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