Genomes and Genes
Summary: Cell surface receptors that bind CORTICOTROPIN; (ACTH, adrenocorticotropic hormone) with high affinity and trigger intracellular changes. Pharmacology suggests there may be multiple ACTH receptors. An ACTH receptor has been cloned and belongs to a subfamily of G-protein-coupled receptors. In addition to the adrenal cortex, ACTH receptors are found in the brain and immune systems.
- Naville D, Barjhoux L, Jaillard C, Faury D, Despert F, Esteva B, et al. Demonstration by transfection studies that mutations in the adrenocorticotropin receptor gene are one cause of the hereditary syndrome of glucocorticoid deficiency. J Clin Endocrinol Metab. 1996;81:1442-8 pubmed..For the mutant receptors, no response to physiological ACTH concentrations was detected, suggesting an impaired binding of ACTH to the receptors and/or an altered coupling to the adenylate cyclase effector. ..
- Chhajlani V. Distribution of cDNA for melanocortin receptor subtypes in human tissues. Biochem Mol Biol Int. 1996;38:73-80 pubmed
- Haynes W, Morgan D, Djalali A, Sivitz W, Mark A. Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic. Hypertension. 1999;33:542-7 pubmed..Our data also suggest that leptin increases renal SNA through activation of hypothalamic melanocortin receptors. In contrast, sympathoactivation to thermogenic BAT by leptin appears to be independent of the melanocortin system. ..
- Chan L, Metherell L, Krude H, Ball C, O Riordan S, Costigan C, et al. Homozygous nonsense and frameshift mutations of the ACTH receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long-term mineralocorticoid deficiency. Clin Endocrinol (Oxf). 2009;71:171-5 pubmed publisher..Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement. ..
- Lee Y, Poh L, Loke K. A novel melanocortin 3 receptor gene (MC3R) mutation associated with severe obesity. J Clin Endocrinol Metab. 2002;87:1423-6 pubmed
- Adan R, Vink T. Drug target discovery by pharmacogenetics: mutations in the melanocortin system and eating disorders. Eur Neuropsychopharmacol. 2001;11:483-90 pubmed..Investigating variations in candidate genes in disease populations appears to be a fruitful approach towards the identification of drug targets. ..
- Shintani M, Ogawa Y, Nakao K. [Obesity induced by abnormality in leptin receptor and melanocortin-4 receptor]. Nihon Rinsho. 2002;60:404-9 pubmed..In this paper, we summarize the clinical characteristics and the mechanisms of obesity caused by genetic abnormalities in leptin receptor and melanocortin-4 receptor. ..
- Funasaka Y, Chakraborty A, Yodoi J, Ichihashi M. The effect of thioredoxin on the expression of proopiomelanocortin-derived peptides, the melanocortin 1 receptor and cell survival of normal human keratinocytes. J Investig Dermatol Symp Proc. 2001;6:32-7 pubmed..Taken together, the results suggest that keratinocyte-derived TRX regulates the expression of stress inducible neuropeptides and their receptor, and is critically involved in the survival of keratinocytes. ..
- Zwermann O, Beuschlein F, Lalli E, Klink A, Sassone Corsi P, Reincke M. Clinical and molecular evidence for DAX-1 inhibition of steroidogenic factor-1-dependent ACTH receptor gene expression. Eur J Endocrinol. 2005;152:769-76 pubmed..These data support the concept that DAX-1 is a major repressor of ACTH-R gene expression in vitro and in vivo. ..
- Holder J, Xiang Z, Bauzo R, Haskell Luevano C. Structure-activity relationships of the melanocortin tetrapeptide Ac-His-D-Phe-Arg-Trp-NH2 at the mouse melanocortin receptors. 4. Modifications at the Trp position. J Med Chem. 2002;45:5736-44 pubmed
- Mogil J, Wilson S, Chesler E, Rankin A, Nemmani K, Lariviere W, et al. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci U S A. 2003;100:4867-72 pubmed
- Schioth H, Lagerström M, Watanobe H, Jonsson L, Vergoni A, Ringholm A, et al. Functional role, structure, and evolution of the melanocortin-4 receptor. Ann N Y Acad Sci. 2003;994:74-83 pubmed..The MC-4 receptor has been remarkably conserved in structure and pharmacology for more than 400 million years, implying that the receptor participated in vital physiological functions early in vertebrate evolution. ..
- Cheung A, Danho W, Swistok J, Qi L, Kurylko G, Franco L, et al. Structure-activity relationship of linear peptide Bu-His-DPhe-Arg-Trp-Gly-NH(2) at the human melanocortin-1 and -4 receptors: arginine substitution. Bioorg Med Chem Lett. 2002;12:2407-10 pubmed..This study unequivocally shows that the positive charge of Arg(8) is not essential for efficient interactions of our pentapeptide with both hMC1R and hMC4R. ..
- Wisse B, Schwartz M, Cummings D. Melanocortin signaling and anorexia in chronic disease states. Ann N Y Acad Sci. 2003;994:275-81 pubmed..The data presented in this paper summarize findings that implicate neuronal melanocortin signaling in inflammatory anorexia. ..
- Flanagan N, Ray A, Todd C, Birch Machin M, Rees J. The relation between melanocortin 1 receptor genotype and experimentally assessed ultraviolet radiation sensitivity. J Invest Dermatol. 2001;117:1314-7 pubmed..Importantly, when analyzed by genotype alone rather than phenotype, the slope of the erythema dose-response differed between those persons who were homozygous or heterozygous mutants and wildtype/pseudo-wildtype (p = 0.026). ..
- Haskell Luevano C, Holder J, Monck E, Bauzo R. Characterization of melanocortin NDP-MSH agonist peptide fragments at the mouse central and peripheral melanocortin receptors. J Med Chem. 2001;44:2247-52 pubmed..This study has also examined to importance of both N- and C-terminal NDP-MSH amino acids at the different melanocortin receptors, providing information for drug design and identification of putative ligand-receptor interactions. ..
- Tachibana T, Sugahara K, Ohgushi A, Ando R, Kawakami S, Yoshimatsu T, et al. Intracerebroventricular injection of agouti-related protein attenuates the anorexigenic effect of alpha-melanocyte stimulating hormone in neonatal chicks. Neurosci Lett. 2001;305:131-4 pubmed..These also imply that the extent of the anorexigenic effect of endogenous alpha-MSH is different among two breeds. This may be a part of the difference in food intake between two breeds. ..
- Prusis P, Muceniece R, Mutule I, Mutulis F, Wikberg J. Design of new small cyclic melanocortin receptor-binding peptides using molecular modelling: Role of the His residue in the melanocortin peptide core. Eur J Med Chem. 2001;36:137-46 pubmed..The data indicate that the His residue of the small rigid cyclic MSH core peptides does not participate in binding with the melanocortin receptors. ..
- Su Y, Rose J. The impact of ACTH receptor knockdown on fetal and adult ovine adrenocortical cell function. Reprod Sci. 2008;15:253-62 pubmed publisher..The data also indicate that a reduction in the ACTH-R expression blocks the ability of the peptide to stimulate early steps in the steroidogenic pathway event after maturation is complete. ..
- Tsiotra P, Koukourava A, Kaltezioti V, Geffner M, Naville D, Begeot M, et al. Compound heterozygosity of a frameshift mutation in the coding region and a single base substitution in the promoter of the ACTH receptor gene in a family with isolated glucocorticoid deficiency. J Pediatr Endocrinol Metab. 2006;19:1157-66 pubmed..In conclusion, we provide evidence that the IGD in this previously unreported family with ACTH resistance appears to be secondary to compound heterozygosity of a coding region and a promoter mutation in the MC2R gene. ..
- Zhong Q, Sridhar S, Ruan L, Ding K, Xie D, Insogna K, et al. Multiple melanocortin receptors are expressed in bone cells. Bone. 2005;36:820-31 pubmed..Thus, in addition to the indirect effects of POMC-derived hormones on bone turnover through their modulation of steroid hormone secretion, POMC fragments may have direct and specific effects on bone cell subpopulations. ..
- Wessells H, Hruby V, Hackett J, Han G, Balse Srinivasan P, Vanderah T. MT-II induces penile erection via brain and spinal mechanisms. Ann N Y Acad Sci. 2003;994:90-5 pubmed..These results provide insight into the central melanocortinergic pathways that mediate penile erection and may allow for more efficacious melanotropin-based therapy for erectile dysfunction. ..
- Prusis P, Muceniece R, Andersson P, Post C, Lundstedt T, Wikberg J. PLS modeling of chimeric MS04/MSH-peptide and MC1/MC3-receptor interactions reveals a novel method for the analysis of ligand-receptor interactions. Biochim Biophys Acta. 2001;1544:350-7 pubmed..Moreover, the cross-terms of the PLS model revealed the existence of a strong interaction between TM6/7 and TM2/3 of the receptors. ..
- Abdel Malek Z, Scott M, Furumura M, Lamoreux M, Ollmann M, Barsh G, et al. The melanocortin 1 receptor is the principal mediator of the effects of agouti signaling protein on mammalian melanocytes. J Cell Sci. 2001;114:1019-24 pubmed..These results indicate that a functional melanocortin 1 receptor is obligatory for the response of mammalian melanocytes to agouti signaling protein. ..
- Mountjoy K, Wu C, Cornish J, Callon K. alpha-MSH and desacetyl-alpha-MSH signaling through melanocortin receptors. Ann N Y Acad Sci. 2003;994:58-65 pubmed
- Lubrano Berthelier C, Durand E, Dubern B, Shapiro A, Dazin P, Weill J, et al. Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet. 2003;12:145-53 pubmed..This result has implications for the potential pharmacologic rescue of childhood obesity-associated MC4R mutations and for the treatment of patients presenting with this condition. ..
- Macintyre D, Glueck S. The proof of the pudding is in the eating: editorial focus on "Hyperphagia, not hypometabolism, causes early onset obesity in melanocortin-4-receptor knockout mice". Physiol Genomics. 2003;13:11-4 pubmed
- Haitina T, Klovins J, Andersson J, Fredriksson R, Lagerström M, Larhammar D, et al. Cloning, tissue distribution, pharmacology and three-dimensional modelling of melanocortin receptors 4 and 5 in rainbow trout suggest close evolutionary relationship of these subtypes. Biochem J. 2004;380:475-86 pubmed
- Schuhler S, Horan T, Hastings M, Mercer J, Morgan P, Ebling F. Decrease of food intake by MC4-R agonist MTII in Siberian hamsters in long and short photoperiods. Am J Physiol Regul Integr Comp Physiol. 2003;284:R227-32 pubmed..lean (SP) states does not support the hypothesis that changes in this melanocortin pathway underlie the long-term decrease in food intake that occurs in this seasonal model. ..
- Latronico A. Role of ACTH receptor in adrenocortical tumor formation. Braz J Med Biol Res. 2000;33:1249-52 pubmed..Deletion of the ACTH-R gene seems to be involved in a subset of human adrenocortical tumors, contributing to cellular dedifferentiation. ..
- Clegg D, Riedy C, Smith K, Benoit S, Woods S. Differential sensitivity to central leptin and insulin in male and female rats. Diabetes. 2003;52:682-7 pubmed..Because insulin and leptin reflect different fat beds and are differentially distributed in the male and female sexes, the implication is that the male and female sexes regulate adiposity-relevant parameters differently. ..
- Chen A, Marsh D, Trumbauer M, Frazier E, Guan X, Yu H, et al. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet. 2000;26:97-102 pubmed..Mice lacking both Mc3r and Mc4r become significantly heavier than Mc4r(-/-) mice. We conclude that Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis. ..
- Ishii T, Ogata T, Sasaki G, Sato S, Kinoshita E, Matsuo N. Novel mutations of the ACTH receptor gene in a female adult patient with adrenal unresponsiveness to ACTH. Clin Endocrinol (Oxf). 2000;53:389-92 pubmed..The present findings lend additional credence to the notions that adrenal androgens play an important role in female pubic hair development and that ovarian development takes place independently of adrenarche. ..
- Lindblom J, Opmane B, Mutulis F, Mutule I, Petrovska R, Klusa V, et al. The MC4 receptor mediates alpha-MSH induced release of nucleus accumbens dopamine. Neuroreport. 2001;12:2155-8 pubmed..This increase was completely blocked by pre-treatment with the MC4 receptor selective antagonist HS131, indicating that the effects of alpha-MSH on dopamine transmission may be mediated by the MC4 receptor. ..
- Morgan C, Thomas R, Ma W, Novotny M, Cone R. Melanocortin-5 receptor deficiency reduces a pheromonal signal for aggression in male mice. Chem Senses. 2004;29:111-5 pubmed..Moreover, farnesene-stimulated aggression is reduced in MC5R-deficient mice, relative to wild-type mice. Our results suggest that activation of the MC5R promotes aggression by increasing farnesene signaling. ..
- Sutton G, Duos B, Patterson L, Berthoud H. Melanocortinergic modulation of cholecystokinin-induced suppression of feeding through extracellular signal-regulated kinase signaling in rat solitary nucleus. Endocrinology. 2005;146:3739-47 pubmed..The cAMP-->ERK-->CREB cascade may thus constitute a molecular integrator for converging satiety signals from the gut and adiposity signals from the hypothalamus in the control of meal size and food intake. ..
- Challis B, Pritchard L, Creemers J, Delplanque J, Keogh J, Luan J, et al. A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Hum Mol Genet. 2002;11:1997-2004 pubmed..These results suggest that the R236G mutation may confer an inherited susceptibility to obesity through the production of an aberrant fusion protein that has the capacity to interfere with central melanocortin signalling. ..
- Benoit S, Air E, Coolen L, Strauss R, Jackman A, Clegg D, et al. The catabolic action of insulin in the brain is mediated by melanocortins. J Neurosci. 2002;22:9048-52 pubmed..These data suggest that the hypothalamic melanocortin system mediates the anorexic effects of central insulin, as well as of leptin. ..
- Swords F, Baig A, Malchoff D, Malchoff C, Thorner M, King P, et al. Impaired desensitization of a mutant adrenocorticotropin receptor associated with apparent constitutive activity. Mol Endocrinol. 2002;16:2746-53 pubmed..These findings suggest a novel mechanism is involved in the apparently constitutive activation of the MC2R in which failure of desensitization appears to be associated with enhanced basal receptor activity. ..
- Baig A, Swords F, Szaszak M, King P, Hunyady L, Clark A. Agonist activated adrenocorticotropin receptor internalizes via a clathrin-mediated G protein receptor kinase dependent mechanism. Endocr Res. 2002;28:281-9 pubmed..In conclusion, it appears that the MC2R in Y1 cells internalizes by a G protein coupled receptor kinase (GRK) dependent clathrin-coated pit mechanism. ..
- Bondebjerg J, Xiang Z, Bauzo R, Haskell Luevano C, Meldal M. A solid-phase approach to mouse melanocortin receptor agonists derived from a novel thioether cyclized peptidomimetic scaffold. J Am Chem Soc. 2002;124:11046-55 pubmed..In addition, some of the compounds showed moderate selectivity for the mMC1R. ..
- Enyeart J, Xu L, Enyeart J. Dual actions of lanthanides on ACTH-inhibited leak K(+) channels. Am J Physiol Endocrinol Metab. 2002;282:E1255-66 pubmed..Allosteric actions of trivalent and divalent metal cations on hormone binding, mediated through Ca(2+)-specific sites, may be common to a variety of peptide hormone receptors...
- Ancans J, Flanagan N, Hoogduijn M, Thody A. P-locus is a target for the melanogenic effects of MC-1R signaling: a possible control point for facultative pigmentation. Ann N Y Acad Sci. 2003;994:373-7 pubmed..These factors together could account for the many different levels of tanning ability seen in the white population. ..
- Yeo G, Lank E, Farooqi I, Keogh J, Challis B, O Rahilly S. Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet. 2003;12:561-74 pubmed
- Li L, Chang Y, Wang C, Tsai F, Jong S, Chung B. Steroidogenic factor 1 differentially regulates basal and inducible steroidogenic gene expression and steroid synthesis in human adrenocortical H295R cells. J Steroid Biochem Mol Biol. 2004;91:11-20 pubmed..Inhibition of SF-1 activity significantly decreased basal expression of ACTH receptor and its induction by potassium and cAMP. ..
- Claycombe K, Xue B, Mynatt R, Zemel M, Moustaid Moussa N. Regulation of leptin by agouti. Physiol Genomics. 2000;2:101-5 pubmed
- Mazzuco T, Grunenwald S, Lampron A, Bourdeau I, Lacroix A. Aberrant hormone receptors in primary aldosteronism. Horm Metab Res. 2010;42:416-23 pubmed publisher..The identification of aberrant adrenal GPCRs by in vivo functional studies offers the potential for novel pharmacological therapies that either suppress the endogenous ligands or block the receptor with specific antagonists. ..
- Wachira S, Hughes Darden C, Nicholas H, Taylor C, Robinson T. Neural melanocortin receptors are differentially expressed and regulated by stress in rat hypothalamic-pituitary-adrenal axis. Cell Mol Biol (Noisy-le-grand). 2004;50:703-13 pubmed
- Vrinten D, Kalkman C, Adan R, Gispen W. Neuropathic pain: a possible role for the melanocortin system?. Eur J Pharmacol. 2001;429:61-9 pubmed..In this way, treatment with melanocortin receptor antagonists might enhance opioid efficacy in neuropathic pain, which would be of great benefit in clinical practice. ..
- Jiang S, Jacobsson L, Kerje S, Andersson L, Xiong Y. [Studies of relationship between the melanocortin-3 receptor gene and body weight in chicken for high and low weight lines' intercross]. Yi Chuan Xue Bao. 2002;29:322-5 pubmed..The result suggests that the MC3R as a candidate gene can explain significant difference for body weight in the intercross chickens. ..
- Luger T, Scholzen T, Brzoska T, Bohm M. New insights into the functions of alpha-MSH and related peptides in the immune system. Ann N Y Acad Sci. 2003;994:133-40 pubmed..Therefore, therapeutic application of alpha-MSH or related peptides (KPVs) as well as alpha-MSH/KPV-pulsed DCs may be a useful approach for the treatment of inflammatory, autoimmune, and allergic diseases in the future. ..
- Skottner A, Post C, Ocklind A, Seifert E, Liutkevicius E, Meskys R, et al. Anti-inflammatory potential of melanocortin receptor-directed drugs. Ann N Y Acad Sci. 2003;994:84-9 pubmed
- Hayward N. Genetics of melanoma predisposition. Oncogene. 2003;22:3053-62 pubmed..Hence, melanoma is turning out to be an excellent paradigm for studying gene-gene and gene-environment interactions. ..