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

A mouse genomic clone named HGMP01B has been isolated by homology screening with a probe representing part of the human melanocortin 3 receptor gene. HGMP01B was found to encode a 325 amino acid protein with all the landmarks of G-protein-coupled receptors and belonging to the growing melanocortin receptor family. This receptor displays four potential sites for N-linked glycosylation and five potential sites of phosphorylation by protein kinase C. The HGMP01B gene was found to be expressed in many tissues, including skin, adrenal gland, skeletal muscle, bone marrow, spleen, thymus, gonads, uterus, and brain. A stable Chinese hamster ovary (CHO) cell line expressing approximately 10,000 receptors per cell was established. This cell line displayed a saturable binding capacity for the radioiodinated alpha-melanocyte-stimulating hormone (alpha-MSH) analog [Nle4,D-Phe7]-alpha-MSH (NDP-MSH) with an apparent Kd of 1.47 +/- 0.15 nM. Binding of the labeled ligand was competed for by all melanocortin peptides, except beta-endorphin or corticotropin-like intermediate lobe peptide (CLIP). NDP-MSH was the most powerful competitor, followed by alpha-MSH, adrenocorticotropic hormone (ACTH), beta-MSH, the gamma-MSHs, and ACTH 4-10. Functional assays confirmed that HGMP01B, like other melanocortin receptors, stimulated adenylyl cyclase. The potency order obtained in these cyclic adenosine monophosphate (cAMP) accumulation assays was consistent with that of the binding studies. HGMP01B therefore appears as a fifth melanocortin receptor (MC5), responding mainly to alpha-MSH (EC50 = 1.07 +/- 0.13 nM) and endowed with a pharmacological profile similar to that of the melanocyte MSH (MC1) receptor, but characterized by a broad tissue distribution.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. 816 9

We describe the cloning of the mouse HGMP01A gene that encodes a melanocortin receptor functionally distinct from the adrenal cortex corticotropin (adrenocorticotrophic hormone; ACTH) receptor and the melanocyte-stimulating hormone (MSH) receptor expressed in melanoma. The gene encodes a protein of 323 amino acids with a calculated molecular mass of 35,800 Da, displaying potential sites for N-linked glycosylation and phosphorylation by protein kinase C. An RNAase protection assay detected weak expression in the brain, but not in adrenal gland, skin, or any of the other tissues tested. Stable CHO cell lines expressing over 100,000 receptors per cell were generated. The recombinant receptor binds iodinated [Nle4,D-Phe7]alpha-MSH (NDP-MSH) with an apparent Kd of 700 pM. Displacement of the ligand by a variety of pro-opiomelanocortin-derived peptides revealed a pharmacological profile distinct from that of the classical ACTH and MSH receptors. NDP-MSH was the most powerful competitor (IC50 1.4 nM), followed by gamma-MSH (IC50 7 nM). alpha-MSH, beta-MSH and ACTH-(1-39) were significantly less potent, with IC50 values of 30, 19 and 21 nM respectively. ACTH-(4-10) was poorly active (IC50 2.4 microM), while corticotropin-like intermediate lobe peptide (CLIP) and beta-endorphin were totally ineffective. The recombinant receptor was found to stimulate adenylate cyclase. The potency order of the agonists in this assay was consistent with that of the binding displacement assays. This receptor represents the orthologue of the human melanocortin 3 receptor reported recently. The growing family of melanocortin receptors constitute the molecular basis for the variety of actions of melanocortins that have been described over the years. The availability of functionally expressed receptors from the melanocortin family will allow the development of a specific pharmacology, and a better understanding of the function of the pro-opiomelanocortin-derived peptides.
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PMID:Molecular cloning, functional expression and pharmacological characterization of a mouse melanocortin receptor gene. 817 96

The existence of multiple brain melanocortin receptor types has been postulated, based on the complex pharmacology of intracerebrally administered melanocortin (melanocyte-stimulating hormone-related) peptides. In this study, this hypothesis was tested by determining whether different brain melanocortin receptor populations can be discriminated on a pharmacologic or neuroanatomic basis. The abilities of various pharmacologically active native melanocortins and structural analogs, as well as other test substances, to compete with biologically active [125I]Nle4,D-Phe7-alpha-MSH ([125I]NDP-MSH) for binding to melanocortin receptors was determined, by in vitro binding and autoradiography in frozen rat brain tissue sections. We have previously shown that native melanocortins including alpha-MSH, gamma-MSH and ACTH1-39 compete with [125I]NDP-MSH for binding to brain tissue sites. In the present studies, each of the melanocortin peptides alpha-MSH, des-acetyl-alpha-MSH, beta-MSH and ACTH1-24 when present at 1 microM virtually eliminated [125I]NDP-MSH binding in each of a series of brain structures, including medial preoptic area, caudate putamen, olfactory tubercle, bed nucleus of the stria terminalis, ventral part of the lateral septal nucleus, hypothalamic periventricular and paraventricular nuclei, dorsal anterior amygdaloid area, substantia innominata and thalamic paraventricular nucleus; as well as in extraorbital lacrimal gland, a peripheral melanocortin target. In contrast, the behaviorally and neurotrophically active melanocortin analogs Met(O2),D-Lys,Phe9-alpha-MSH4-9 (Org2766), ACTH4-9, and the antipyretic peptide alpha-MSH11-13 did not affect [125I]NDP-MSH binding at concentrations up to 100 microM, implying that the receptors or receptor binding sites which mediate the actions of these analogs must comprise additional types, distinct from those which bind [125I]NDP-MSH. Binding of [125I]NDP-MSH was also unaffected by the nonmelanotropic peptides ACTH1-4, ACTH34-39 and vasoactive intestinal polypeptide (VIP) and by the antipyretic drugs acetaminophen and lysine-salicylate. Although some of the brain structures are known to express mRNA encoding a gamma-MSH-preferring melanocortin receptor type known as MC3, the relative order of binding affinities of melanocortins, determined in concentration-response studies, was NDP-MSH > or = ACTH1-24 > or = alpha-MSH > gamma-MSH > ACTH4-10 in all brain structures. This suggests that other melanocortin receptor type(s) in addition to MC3 probably account for most of the [125I]NDP-MSH binding detectable in the brain.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Heterogeneity of brain melanocortin receptors suggested by differential ligand binding in situ. 817 50

We undertook these studies to explore the intracellular signaling mechanisms activated by a newly described human brain melanocortin receptor (hMC3R). Hepa cells transfected with the hMC3R gene responded to stimulation with alpha-melanocyte stimulation hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH) with dose-dependent increases in cellular content of cyclic 3',5'-adenosine monophosphate (cAMP) reaching a maximum of over 1500% of control cells at the 10(-8) M dose (EC50 = 10(-11) M). In contrast, the production of [3H]inositol phosphates in cells prelabeled with myo-[2-3H]inositol exhibited a biphasic dose-response curve with increases as high as 155% of basal at 10(-11) M alpha-MSH or ACTH, but beyond that a dose-dependent decrease was observed. The inhibitory component of the dose-response curve could be abolished by pretreatment of transfected cells with the cAMP antagonist (Rp)-adenosine 3',5'-monophosphorothioate (Rp-cAMP) or the protein kinase A inhibitor H-89. Increases in intracellular calcium induced in transfected cells by alpha-MSH in doses ranging from 10(-11) to 10(-7) M could not be observed unless the cells were pretreated with H-89. By replacing the third intracytoplasmic loop of the canine H2-histamine receptor with that of hMC3R the biphasic characteristic of agonist-induced production of [3H]inositol phosphates was conferred to the chimeric receptor. These data indicate that the hMC3R is coupled to both cAMP and inositol phospholipid/Ca(2+)-mediated post-receptor signaling systems and that the latter response is regulated by protein kinase A activity.
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PMID:Interaction of dual intracellular signaling pathways activated by the melanocortin-3 receptor. 817 43

Adrenocorticotropic hormone (ACTH) and melanocortin peptides (alpha, beta and gamma MSH) have numerous activities in both central nervous system and peripheral tissues, namely the adrenals. Recently, five melanocortin receptors were cloned and characterized. We report here the cloning, pharmacological characterization and expression of the rat fifth melanocortin receptor (MC5), starting from the dopamine D3 receptor sequence to screen a genomic DNA library. The MC5 comprises a sequence of 325 amino acids, displaying 45-62% identity with other melanocortin receptors and 82% identity with its human counterpart that we cloned thereafter. The sequence of the latter is identical to that of a so-called 'MC2' receptor (Chhajlani et al., 1993, Biochem. Biophys. Res. Comm. 195, 866-873). The MC5, stably expressed in CHO cells, mediates increase in cAMP accumulation with a characteristic pharmacology: alpha MSH is twice as potent as NDP alpha MSH, 10 times as ACTH and 100 times as gamma MSH. Very low expression levels were detected in brain, while high levels were found in adrenals, stomach, lung and spleen. In addition, in situ hybridization studies show the MC5 expressed in the three layers of the adrenal cortex, predominantly in the aldosterone-producing zona glomerulosa cells.
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PMID:Molecular cloning and characterization of the rat fifth melanocortin receptor. 817 77

Recent studies have revealed the presence of four subtypes for the melanocortin receptor (MC-R). Among these MC-Rs, MC2-R is considered to be an adrenocorticotropin (ACTH) receptor because its expression is almost localized in the adrenal cortex. Five Japanese patients with ACTH unresponsiveness were examined as to whether they have mutations in the putative ACTH receptor. Among these patients, there are two groups of siblings, each of which consists of two individuals. The coding region of the ACTH receptor gene was amplified by polymerase chain reaction and directly sequenced on both strands, however, no point mutation was found in any of the five patients, suggesting that familial glucocorticoid deficiency, caused by the mutated ACTH receptor, may be rare.
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PMID:[Adrenocorticotropin receptor in familial glucocorticoid deficiency]. 825 33

A human genomic clone designated MC-2 is isolated. The cloned DNA codes for a protein of 325 amino acids which possesses seven hydrophobic segments, a characteristic of G-protein coupled receptors. The MC-2 receptor is expressed in brain tissue but not in the melanoma cells. When the MC-2 DNA is expressed in COS-7 cells, it binds [125I]-labelled [Nle4, D-Phe7]- alpha melanocyte stimulating hormone (NDP-MSH) which then could be displaced by melanotropic peptides alpha-MSH, beta-MSH, gamma-MSH and adrenocorticotropic hormone, but not by non-melanotropic peptide beta-endorphin. The highest affinity of 5.18 nM was for the NDP-MSH peptide. The novel MC-2 receptor and the MC-1 receptor, described earlier by us (8) showed identical order of affinity for the melanocortin peptides, but the affinities and the fold differences in the affinities to the melanocortin peptides were different when compared to the earlier described MC-1 receptor. The results suggest that the MC-2 DNA codes for a novel melanocortin receptor.
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PMID:Molecular cloning of a novel human melanocortin receptor. 856 9

Corticotropin (ACTH) and melanotropin (MSH) peptides (melanocortins) are produced not only in the pituitary but also in the brain, with highest concentrations in the arcuate nucleus of the hypothalamus and the commisural nucleus of the solitary tract. We have identified a receptor for MSH and ACTH peptides that is specifically expressed in regions of the hypothalamus and limbic system. This melanocortin receptor (MC3-R) is found in neurons of the arcuate nucleus known to express proopiomelanocortin (POMC) and in a subset of the nuclei to which these neurons send projections. The MC3-R is 43% identical to the MSH receptor present in melanocytes and is strongly coupled to adenylyl cyclase. Unlike the MSH or ACTH receptors, MC3-R is potently activated by gamma-MSH peptides, POMC products that were named for their amino acid homology with alpha- and beta-MSH, but lack melanotropic activity. The primary biological role of the gamma-MSH peptides is not yet understood. The location and properties of this receptor provide a pharmacological basis for the action of POMC peptides produced in the brain and possibly a specific physiological role for gamma-MSH.
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PMID:Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. 841 20

Variation in the degree of prolonged (residual) biological activity of the melanotropin peptides alpha-MSH (alpha-melanocyte-stimulating hormone, Ac-Ser-Tyr-Met-Glu- His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and the superpotent analogues [Nle4,DPhe7]alpha-MSH (MT-I) and Ac-[Nle4,Asp5,DPhe7,Lys10]alpha-MSH(4-10-NH2 (MT-II) has stimulated considerable interest regarding this biological phenomena. We have examined the differences in their relative dissociation rates from the melanocortin receptor, hMC1R, to try and correlate peptide dissociation rates with the observations of prolonged biological activity. Interestingly, these studies revealed that alpha-MSH remained 25% bound, MT-I 65% bound, and MT-II 86% bound 6 h after the ligand had been removed from the assay medium. The relative dissociation rate of MT-II was 4 times slower than that for alpha-MSH and 2 times slower than that for MT-I, which was 2 times slower than that for alpha-MSH. These data suggest that slow dissociation kinetics (hours) may contribute to the prolonged biological activities observed for both MT-I and MT-II peptides in vitro and in vivo. The prolonged binding, biological activities, and enzymatic stability of MT-I and MT-II make them putative candidates for clinical uses such as external scintigraphy for the localization of tumors (i.e., melanoma).
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PMID:Characterizations of the unusual dissociation properties of melanotropin peptides from the melanocortin receptor, hMC1R. 855 11

Agouti protein is known to antagonize cAMP formation, tyrosinase activation and melanogenesis in mouse B16-F1 melanoma cells induced by alpha-melanocyte-stimulating hormone (alpha-MSH). We now demonstrate that although agouti binds to the melanocortin receptor MC1-R with an almost identical affinity to that of alpha-MSH, it does not antagonize the inhibitory action of alpha-MSH on the growth of B16-F1 cells. Instead it has a similar antiproliferative action with a half-maximal effective concentration of 13 nM. In G4F cells lacking MC1-R, agouti is without effect. Agouti was also found to induce MC1-R down-regulation with identical kinetics and magnitude as alpha-MSH. Thus, the different effects of agouti on B16-F1 cells proceed via interaction with MC1-R but are not exclusively antagonistic.
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PMID:Agouti protein inhibits growth of B16 melanoma cells in vitro by acting through melanocortin receptors. 857 26


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