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)

We have examined the possible linkage of adrenocorticotropin receptor/melanocortin receptor-2 (ACTHR/MC-2) to a reported putative susceptibility locus for bipolar illness (BP) in 20 affected pedigrees. Initially, allelic variants of the gene were identified by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) and the gene was genetically mapped using both the Centre d'Etudes du Polymorphisme Humain (CEPH) pedigrees and the BP pedigrees used in this study. We found that the ACTHR/MC-2 gene maps between D18S53 and D18S66. These loci span a region of chromosome 18 which, in a previous study [Berrettini et al.: Proc Natl Acad Sci USA 91:5918-5921, 1994) revealed a putative predisposing locus to BP through nonparametric methods of linkage analysis. Linkage of ACTHR/MC-2 to BP was not demonstrable under parametric and nonparametric methods of analyses, although affected sib-pair (ASP) method revealed an increase in allele sharing among ill individuals, P = 0.023. Since this receptor is within a potential linkage region, ACTHR/MC-2 could be considered a candidate gene for BP.
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PMID:Adrenocorticotropin receptor/melanocortin receptor-2 maps within a reported susceptibility region for bipolar illness on chromosome 18. 748 68

Several dominant mutations at the murine agouti locus result in the expression of a number of phenotypic changes, including a predominantly yellow coat color, obesity, and hyperinsulinemia. The mutants exhibit ectopic overexpression of normal agouti protein, suggesting that agouti regulates coat coloration by direct antagonism of the alpha-melanocyte-stimulating hormone receptor. We have tested this hypothesis by examining agouti inhibition of both melanocortin-stimulated cyclic adenosine monophosphate production and the binding of a radioactive melanocortin analog in the murine B16F10 melanoma cell line. Inhibition of melanocortin-induced cyclic nucleotide accumulation did not require preincubation of the cells with agouti and was independent of the agonist used. Furthermore, inhibition of both agonist binding to and activation of melanocortin receptor could be described by a simple competitive model with similar inhibition constants of 1.9 and 0.9 nM, respectively. The mutually exclusive binding of agouti and melanocortin was verified by cross-linking experiments using a radiolabeled alpha-melanocyte-stimulating hormone analog. Competitive inhibition of alpha-melanocyte-stimulating hormone binding can account for the effects of agouti on coat coloration and suggests the possibility that the other phenotypic changes observed on agouti overexpression may be due to direct action of agouti at a novel melanocortin receptor(s).
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PMID:Agouti antagonism of melanocortin binding and action in the B16F10 murine melanoma cell line. 754 13

The melanocortin (MC) peptides mediate a diverse spectrum of biological activities in both the central nervous system and peripheral tissues by interacting with specific guanine nucleotide binding (G protein)-coupled receptors. Previously, four human melanocortin receptor subtypes have been cloned and characterized. In this study, we have isolated mouse complementary DNA (cDNA) and human genomic clones encoding a fifth melanocortin receptor subtype, MC5. Melanocortin peptide stimulation of human MC5, transiently expressed in COS1 cells, results in activation of adenylate cyclase with the following rank order of potency: [Nle4, D-Phe7]-alpha-MSH (melanocyte stimulating hormone) > ACTH (1-24) (adrenocorticotropic hormone) > alpha-MSH > beta-MSH > gamma-MSH. Northern blot hybridization, ribonuclease protection, and reverse transcription/polymerase chain reaction assays indicate that mouse MC5 mRNA is most abundant in skeletal muscle and brain. Lower but detectable levels of MC5 mRNA are also found in RT2-2 retinal neuronal cells, lung, testis, spleen, heart, kidney, and liver.
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PMID:Cloning, expression, and tissue distribution of a fifth melanocortin receptor subtype. 773 52

The DNAs encoding three melanocortin receptor subtypes (melanocortin MC1 receptor, melanocortin MC3 receptor and melanocortin MC5 receptor) were expressed individually in COS (CV-1 Origin, SV40) cells to characterise their ligand binding properties. The results indicated that [125I][Nle4, D-Phe7]alpha-MSH (melanocyte stimulating hormone) bound to a single saturable site with Kd values of 85.1 +/- 8.0 pmol/l (mean +/- S.E.M), 396 +/- 65 pmol/l and 5.05 +/- 1.00 nmol/l for melanocortin MC1 receptor, melanocortin MC3 receptor and melanocortin MC3 receptor, respectively. The melanocortin MC1 receptor and the melanocortin MC5 receptor showed a similar potency order to the melanocortic peptides examined which was markedly different from the potency order of the melanocortin MC3 receptor. The melanocortin MC1 receptor and melanocortin MC5 receptor had a relatively higher affinity for alpha-MSH than gamma-MSH and beta-MSH, whereas the melanocortin MC3 receptor had higher affinity for desacetyl-alpha-MSH, gamma-MSH and beta-MSH compared to alpha-MSH. The inclusion of the endopeptidase inhibitor phosphoramidon to prevent the breakdown of ACTH-(1-39) (adrenocorticotrophic hormone) to alpha-MSH, decreased ACTH-(1-39) binding affinity showing that ACTH-(1-39) had a much lower affinity for melanocortin MC1 receptor than reported earlier.
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PMID:Characterisation of melanocortin receptor subtypes by radioligand binding analysis. 777 75

The influence of single amino acid replacements by alanine on the binding affinity and biological activity of alpha-MSH in B16 murine melanoma cells has been studied systematically. alpha-MSH analogues were synthesized by solid-phase peptide synthesis and their binding affinities to the melanocortin receptor expressed by B16 mouse melanoma cells were determined using a radioreceptor assay. Biological activity of the analogues was determined by measuring tyrosinase stimulation. Relative activity and affinity data were generally in agreement with earlier results using terminal deletion fragments of alpha-MSH, but the alanine scan revealed important new insights into the role of individual residues. The three terminal amino acids at either end were not necessary for binding or activity, with amino acids 4-9 forming a core sequence required for receptor binding and triggering of the biological response. It was observed that replacement of the glutamic acid residue in position 5 was possible without loss of affinity or activity, whereas replacement of Met4 resulted in a 100-fold loss of binding affinity and biological activity. Each residue within the conserved melanocortin sequence His-Phe-Arg-Trp was shown to be essential with Phe7, Arg8, and Trp9 being the most sensitive to replacement by alanine. Generally, there was a rank correlation between binding affinity and tyrosinase stimulation within the group of analogues studied. Tyrosinase activity was less affected by alanine substitution than binding affinity, which suggests that full receptor binding is not required for maximum biological response.
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PMID:Synthesis and biological evaluation of alpha-MSH analogues substituted with alanine. 785 84

Antagonists for the melanocortin receptor family were identified by analysis of the effects of four melanocortin analogues on alpha-MSH(alpha-melanocyte-stimulating hormone)-induced cAMP accumulation in 293 human embryonal kidney (HEK) cells that expressed either the rat melanocortin MC3 receptor, the human melanocortin MC4 receptor or the ovine melanocortin MC5 receptor. Two peptides, [D-Arg8]ACTH(adrenocorticotrope hormone)-(4-10) and [Pro8,10,Gly9]ACTH-(4-10), antagonized the action of alpha-MSH on the melanocortin MC4 and MC5 receptors, but not the melanocortin MC3 receptor. [Ala6]ACTH-(4-10) inhibited the alpha-MSH activation of the melanocortin MC3 and MC5, but only weakly antagonized the activation of the melanocortin MC4 receptor. [Phe-I7]ACTH-(4-10) antagonized the melanocortin MC3, MC4 and MC5 receptors equally well. These antagonists were also tested to block a behavioral response induced by alpha-MSH. alpha-MSH-induced excessive grooming behavior in rats was inhibited by [Phe-I7]ACTH-(4-10), [D-Arg8]ACTH-(4-10) and [Pro8,10,Gly9]ACTH-(4-10), but not by [Ala6]ACTH-(4-10). This suggests that alpha-MSH-induced excessive grooming behavior is mediated by melanocortin MC4 receptors.
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PMID:Identification of antagonists for melanocortin MC3, MC4 and MC5 receptors. 789 72

The genetic loci agouti and extension control the relative amounts of eumelanin (brown-black) and phaeomelanin (yellow-red) pigments in mammals: extension encodes the receptor for melanocyte-stimulating hormone (MSH) and agouti encodes a novel 131-amino-acid protein containing a signal sequence. Agouti, which is produced in the hair follicle, acts on follicular melanocytes to inhibit alpha-MSH-induced eumelanin production, resulting in the subterminal band of phaeomelanin often visible in mammalian fur. Here we use partially purified agouti protein to demonstrate that agouti is a high-affinity antagonist of the MSH receptor and blocks alpha-MSH stimulation of adenylyl cyclase, the effector through which alpha-MSH induces eumelanin synthesis. Agouti was also found to be an antagonist of the melanocortin-4 receptor, a related MSH-binding receptor. Consequently, the obesity caused by ectopic expression of agouti in the lethal yellow (Ay) mouse may be due to the inhibition of melanocortin receptor(s) outside the hair follicle.
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PMID:Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. 793 41

Binding and stimulation of cAMP by the melanotropin peptides alpha-MSH (alpha-melanocyte-stimulating hormone) and its superpotent analogues [Nle4, DPhe7]alpha-MSH (MT-I) and Ac-[Nle4,[formula: see text]alpha-MSH4-10-NH2 (MT-II) were undertaken to examine their respective properties on the human peripheral melanocyte melanocortin receptor, hMC1R. alpha-MSH was found to possess a binding IC50 value of 6.5 +/- 0.9 x 10(-9) M and cAMP EC50 value of 2.0 +/- 0.6 x 10(-9) M. MT-I possesses a binding IC50 value of 1.2 +/- 0.3 x 10(-9) M and a cAMP EC50 of 0.5 +/- 0.03 x 10(-9) M. MT-II possesses a binding IC50 of 0.57 +/- 0.08 x 10(-9) M and cAMP EC50 value of 0.20 +/- 0.05 x 10(-9) M.
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PMID:Binding and cAMP studies of melanotropin peptides with the cloned human peripheral melanocortin receptor, hMC1R. 798 May 88

A new member of the G protein-coupled receptor superfamily has been isolated from an ovine genomic library with a probe generated by the application of the PCR technique, using cDNA synthesized on a mRNA template isolated from the ovine pars tuberalis. This genomic clone encodes a novel receptor of 325 amino acids with seven transmembrane domains. These domains share homology with other members of this family, but the best homology is with the recently cloned human MC-1 (50% in the transmembrane domains) and MC-3 (69% in the transmembrane domains) MSH receptors and the human ACTH (42% in the transmembrane domains) receptor. When this receptor was expressed in Cos7 cells, it was able to bind a potent analogue of alpha-MSH, [Nle4,D-Phe7]-alpha-MSH (NDP-MSH), with high affinity. This binding could be displaced by pro-opiomelanocortin-derived and related peptides, with the order of potency NDP-MSH > alpha-MSH = ACTH > beta-MSH and with no effect of gamma-MSH, delta-MSH or beta-endorphin. The expressed receptor was demonstrated to be functionally coupled to the adenylate cyclase second messenger pathway, with alpha-MSH, beta-MSH and ACTH stimulating cyclic AMP production. The amount of the mRNA for this receptor was found to be very low. The tissue distribution of this receptor could only be observed using the reverse transcription-PCR technique and the receptor was found to be present in a number of somatic tissues. These data indicate that this is a new and distinct member of the melanocortin receptor family.
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PMID:Cloning and expression of a new member of the melanocyte-stimulating hormone receptor family. 806 Apr 85

Membrane preparations of cells expressing the cloned rat hypothalamus melanocortin receptor, MC3, have been photoaffinity labelled using a radiolabelled photoreactive analogue of alpha-MSH, [125I-Tyr2,Nle4,D-Phe7,ATB-Lys11]alpha-MSH. SDS-PAGE followed by autoradiography showed a single band at 53-56 kDa for the native receptor or 35 kDa after deglycosylated with PNGase F, consistent with the predicted cDNA sequence. Receptor binding studies with alpha-MSH, gamma-MSH and [Nle4,D-Phe7]alpha-MSH established that alpha-MSH and gamma-MSH had similar affinities while [Nle4,D-Phe7]alpha-MSH bound 100 times more strongly. These results suggest that the receptor recognises the conserved 'core sequence' (-Met-Glu/Gly-His-Phe-Arg-Trp-) of MSH/ACTH peptides. The binding affinities of alanine-substituted analogues of alpha-MSH were determined to investigate the role of individual residues in ligand-receptor interactions. While in the terminal regions only the replacement of Tyr2 reduced the affinity of the peptide, replacement of Met4, Phe7, Arg8 and Trp9 within the peptide core led to a significant loss of affinity. Glu5 appeared unimportant for receptor recognition.
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PMID:The melanocortin (MC3) receptor from rat hypothalamus: photoaffinity labelling and binding of alanine-substituted alpha-MSH analogues. 806 18


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