Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The processed products of the proopiomelanocortin gene (ACTH, alpha-MSH, beta-MSH, gamma-MSH, etc.) interact with five melanocortin receptors, the MC1R, MC2R, MC3R, MC4R, and MC5R to modulate and control many important biological functions crucial for good health both peripherally (as hormones) and centrally (as neurotransmitters). Pivotal biological functions include pigmentation, adrenal function, response to stress, fear/flight, energy homeostasis, feeding behavior, sexual function and motivation, pain, immune response, and many others, and are believed to be involved in many disease states including pigmentary disorders, adrenal disorders, obesity, anorexia, prolonged and neuropathic pain, inflammatory response, etc. The melanocortin-3 receptor (MC3R) is found primarily in the brain and spinal cord and also in the periphery, and its biological functions are still not well understood. Here we review some of the biological functions attributed to the MC3R, and then examine in more detail efforts to design and synthesize ligands that are potent and selective for the MC3R, which might help resolve the many questions still remaining about its function. Though some progress has been made, there is still much to be done in this critical area.
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PMID:Design, synthesis and biological evaluation of ligands selective for the melanocortin-3 receptor. 1758 28

The precursor protein, proopiomelanocortin (POMC), produces many biologically active peptides via a series of enzymatic steps in a tissue-specific manner, yielding the melanocyte-stimulating hormones (MSHs), corticotrophin (ACTH) and beta-endorphin. The MSHs and ACTH bind to the extracellular G-protein coupled melanocortin receptors (MCRs) of which there are five subtypes. The MC3R and MC4R show widespread expression in the central nervous system (CNS), whilst there is low level expression of MC1R and MC5R. In the CNS, cell bodies for POMC are mainly located in the arcuate nucleus of the hypothalamus and the nucleus tractus solitarius of the brainstem. Both of these areas have well defined functions relating to appetite and food intake. Mouse knockouts (ko) for pomc, mc4r and mc3r all show an obese phenotype, as do humans expressing mutations of POMC and MC4R. Recently, human subjects with specific mutations in beta-MSH have been found to be obese too, as have mice with engineered beta-endorphin deficiency. The CNS POMC system has other functions, including regulation of sexual behaviour, lactation, the reproductive cycle and possibly central cardiovascular control. However, this review will focus on feeding behaviour and link it in with the neuroanatomy of the POMC neurones in the hypothalamus and brainstem.
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PMID:The role of proopiomelanocortin (POMC) neurones in feeding behaviour. 1776 72

ACTH (i.e., corticotropin) is the principal regulator of the hypothalamus-pituitary-adrenal axis and stimulates steroidogenesis in the adrenal gland via the specific cell-surface melanocortin 2 receptor (MC2R). Here, we generated mice with an inactivation mutation of the MC2R gene to elucidate the roles of MC2R in adrenal development, steroidogenesis, and carbohydrate metabolism. These mice, the last of the knockout (KO) mice to be generated for melanocortin family receptors, provide the opportunity to compare the phenotype of proopiomelanocortin KO mice with that of MC1R-MC5R KO mice. We found that the MC2R KO mutation led to neonatal lethality in three-quarters of the mice, possibly as a result of hypoglycemia. Those surviving to adulthood exhibited macroscopically detectable adrenal glands with markedly atrophied zona fasciculata, whereas the zona glomerulosa and the medulla remained fairly intact. Mutations of MC2R have been reported to be responsible for 25% of familial glucocorticoid deficiency (FGD) cases. Adult MC2R KO mice resembled FGD patients in several aspects, such as undetectable levels of corticosterone despite high levels of ACTH, unresponsiveness to ACTH, and hypoglycemia after prolonged (36 h) fasting. However, MC2R KO mice differ from patients with MC2R-null mutations in several aspects, such as low aldosterone levels and unaltered body length. These results indicate that MC2R is required for postnatal adrenal development and adrenal steroidogenesis and that MC2R KO mice provide a useful animal model by which to study FGD.
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PMID:Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis. 1798 25

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)-alpha-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.
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PMID:Melanocortin-1 receptor signaling markedly induces the expression of the NR4A nuclear receptor subgroup in melanocytic cells. 1829 87

Alpha-melanocyte stimulating hormone (alpha-MSH) and other melanocortins make up a family of endogenous peptides derived from pro-opiomelanocortin. Through binding to five melanocortin receptors (MCR), these peptides exert multiple influences on the host, including anti-inflammatory and immunomodulatory effects. The wide distribution of at least three melanocortin receptor subtypes (MC1R, MC3R and MC4R) in neural, glial and endothelial cells suggests that these receptors could be pharmacological targets for neuroprotective therapies. As a consequence of modulation of NF-kappaB-mediated transcription, melanocortins reduce production of pro-inflammatory agents in brain cells after injury. During brain ischemia, alpha-MSH and other melanocortins exert protective influences with a broad time window. Further, melanocortins rescue neurons subjected to excitotoxic insults, accelerate neurophysiological recovery after spinal cord injury and increase regenerative capacity of peripheral nerves in postlesion repair. Based on their established actions, melanocortins could form a novel class of therapeutic agents for acute and chronic disorders of the nervous system.
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PMID:Neuroprotective actions of melanocortins: a therapeutic opportunity. 1855 Jan 83

In this study we set out to ascertain whether melanocortin peptides could be potential therapeutic agents in allergic and non-allergic models of lung inflammation by identifying the receptor(s) involved using a molecular, genetic and pharmacological approach. Western blot analyses revealed expression of the melanocortin receptor (MCR) type 1 and 3 on alveolar macrophages from wild-type mice. Alveolar macrophage incubation, with the selective MC3R agonist [D-TRP(8)]-gamma-MSH and pan-agonist alpha-MSH but not the selective MC1R agonist MS05, led to an increase in cAMP in wild-type macrophages. This increase occurred also in macrophages taken from recessive yellow (e/e; bearing a mutant and inactive MC1R) mice but not from MC3R-null mice. In an allergic model of inflammation, the pan-agonist alpha-MSH and selective MC3R agonist [D-TRP(8)]-gamma-MSH displayed significant attenuation of both eosinophil and lymphocyte accumulation but not IL-5 levels in wild-type and recessive yellow e/e mice. However in MC3R-null mice, alpha-MSH failed to cause a significant inhibition in these parameters, highlighting a preferential role for MC3R in mediating the anti-inflammatory effects of melanocortins in this model. Utilising a non-allergic model of LPS-induced lung neutrophilia, the pan-agonist alpha-MSH and selective MC3R agonist [D-TRP(8)]-gamma-MSH displayed significant attenuation of neutrophil accumulation and inhibition of TNF-alpha release. Thus, this study highlights that melanocortin peptides inhibit leukocyte accumulation in a model of allergic and non-allergic inflammation and this protective effect is associated with activation of the MC3R. The inhibition of leukocyte accumulation is via inhibition of TNF-alpha in the non-allergic model of inflammation but not IL-5 in the allergic model. These data have highlighted the potential for selective MC3R agonists as novel anti-inflammatory therapeutics in lung inflammation.
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PMID:A role for MC3R in modulating lung inflammation. 1899 58

Interleukin-1beta (IL-1beta) significantly influences memory consolidation. Treatments that raise the level of IL-1beta in the brain, given after training, impair contextual fear conditioning. The melanocortin alpha-MSH exerts potent anti-inflammatory actions by physiologically antagonizing the effect of pro-inflammatory cytokines. Five subtypes of melanocortin receptors (MC1R-MC5R) have been identified, with MC3R and MC4R predominating in the central nervous system. The present experiments show that injection of IL-1beta (5 ng/0.25 microl) in dorsal hippocampus up to 15 min after training decreased freezing during the contextual fear test. The treatment with IL-1beta (5 ng/0.25 microl) 12h after conditioning cause amnesia when animals were tested 7 days post training. Thus, our results also demonstrated that IL-1beta can influence persistence of long-term memory. We determined that animals previously injected with IL-1beta can acquire a new contextual fear memory, demonstrating that the hippocampus was not damaged. Treatment with alpha-MSH (0.05 microg/0.25 microl) blocked the effect of IL-1beta on contextual fear memory. Administration of the MC4 receptor antagonist HS014 (0.5 microg/0.25 microl) reversed the effect of alpha-MSH. However, treatment with gamma-MSH (0.5 microg/0.25 microl), an MC3 agonist, did not affect IL-1beta-induced impairment of memory consolidation. These results suggest that alpha-MSH, through central MC4R can inhibit the effect of IL-1beta on memory consolidation.
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PMID:Memory impairment induced by IL-1beta is reversed by alpha-MSH through central melanocortin-4 receptors. 1927 30

The melanocortin receptor (MCR) family consists of 5 G protein-coupled receptors (MC1R-MC5R) with diverse physiologic roles. MC2R is a critical component of the hypothalamic-pituitary-adrenal axis, whereas MC3R and MC4R have an essential role in energy homeostasis. Mutations in MC4R are the single most common cause of monogenic obesity. Investigating the way in which these receptors signal and traffic to the cell membrane is vital in understanding disease processes related to MCR dysfunction. MRAP is an MC2R accessory protein, responsible for adrenal MC2R trafficking and function. Here we identify MRAP2 as a unique homologue of MRAP, expressed in brain and the adrenal gland. We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). Collectively, our data identify MRAP and MRAP2 as unique bidirectional regulators of the MCR family.
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PMID:MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family. 1932 86

More than 150 genes have been identified that affect skin color either directly or indirectly, and we review current understanding of physiological factors that regulate skin pigmentation. We focus on melanosome biogenesis, transport and transfer, melanogenic regulators in melanocytes, and factors derived from keratinocytes, fibroblasts, endothelial cells, hormones, inflammatory cells, and nerves. Enzymatic components of melanosomes include tyrosinase, tyrosinase-related protein 1, and dopachrome tautomerase, which depend on the functions of OA1, P, MATP, ATP7A, and BLOC-1 to synthesize eumelanins and pheomelanins. The main structural component of melanosomes is Pmel17/gp100/Silv, whose sorting involves adaptor protein 1A (AP1A), AP1B, AP2, and spectrin, as well as a chaperone-like component, MART-1. During their maturation, melanosomes move from the perinuclear area toward the plasma membrane. Microtubules, dynein, kinesin, actin filaments, Rab27a, melanophilin, myosin Va, and Slp2-a are involved in melanosome transport. Foxn1 and p53 up-regulate skin pigmentation via bFGF and POMC derivatives including alpha-MSH and ACTH, respectively. Other critical factors that affect skin pigmentation include MC1R, CREB, ASP, MITF, PAX3, SOX9/10, LEF-1/TCF, PAR-2, DKK1, SCF, HGF, GM-CSF, endothelin-1, prostaglandins, leukotrienes, thromboxanes, neurotrophins, and neuropeptides. UV radiation up-regulates most factors that increase melanogenesis. Further studies will elucidate the currently unknown functions of many other pigment genes/proteins. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.
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PMID:Physiological factors that regulate skin pigmentation. 1944 48

There is growing evidence to suggest that proopiomelanocortin (POMC), a precursor of adrenocorticotropin and alpha-melanocyte-stimulating hormone (alpha-MSH), also exists in extrapituitary organs, including immune organs. We investigated the presence of the POMC signaling system in the avian-specific primary immune organ the bursa of Fabricius (BF) of the adult quail. Immunohistochemical staining revealed the presence of cells showing immunopositive reaction with anti-alpha-MSH antibody in the quail specimens. RT-PCR analysis revealed the expression of POMC, prohormone convertases (PC1/3 and PC2), and three melanocortin receptor subtype (MC1R, MC4R, and MC5R) mRNAs in total RNA specimens of the BF. These findings demonstrate that in the quail BF, just as in the pituitary, immunopositive alpha-MSH substances may be produced via specific cleavages of POMC by the sequential actions of PC1/3 and PC2. The observation of MCR expression within the BF suggests that the alpha-MSH substances may exert paracrine actions within the BF.
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PMID:Demonstration of the proopiomelanocortin signaling system in the primary immune organ of the quail. 1945 81


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