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)

alpha-Melanocyte stimulating hormone (alpha-MSH) and ACTH increase the proliferation and melanogenesis of cultured human melanocytes. To further analyze how melanotropins produce these biological effects, we investigated the regulation of the melanocortin receptor MC1R expression by alpha-MSH and ACTH using Northern blot analysis and determine the relative affinity of the receptor for the structurally similar peptides alpha-MSH, ACTH, beta-MSH, and gamma-MSH. We also determined the relative potencies of these hormones to stimulate cAMP formation, tyrosinase activity, and melanocyte proliferation. The order of affinity and potency of the noted melanotropins in these assays were alpha-MSH = ACTH > beta-MSH > gamma-MSH. Because the binding affinity of each of these melanotropins for the MC1R correlated with its ability to stimulate human melanocyte proliferation and melanogenesis, we conclude that these effects are mediated specifically by binding to and activation of the MC1R. gamma-MSH stimulated cAMP formation without affecting proliferation or melanogenesis. However, we found that relative to alpha-MSH, the effect of gamma-MSH on cAMP formation was transient. Our results suggest that alpha-MSH, ACTH, and possibly beta-MSH, but not gamma-MSH, are capable of a physiological role in regulating human pigmentation, and that melanocytes in human skin are a specific target for these hormones.
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PMID:Binding of melanotropic hormones to the melanocortin receptor MC1R on human melanocytes stimulates proliferation and melanogenesis. 861 94

It has been known for many years that adipocytes express high affinity ACTH and alpha-melanocyte stimulating hormone (MSH) binding sites, and that ACTH, alpha-MSH, and beta-lipotropin are potent lipolytic hormones. We show here that the adipocyte response to the melanocortin peptides results from the expression of both the MC2 (ACTH) receptor as well as the newly discovered MC5 receptor. Using RT-PCR and Northern blot hybridization, high levels of MC2 receptor messenger RNA (mRNA) were found in all adipose tissues examined in the mouse, whereas MC5 receptor mRNA was found in a subset of these. Both receptors mRNAs were also found in the 3T3-L1 cell line but only after the cells had been induced to differentiate into adipocytes. This cell line was then used to characterize the pharmacological properties of the MC2 and MC5 receptor sites in situ. The MC2 receptor exhibits properties similar to the ACTH receptor characterized in adrenocortical cells, coupling to activation of adenylyl cyclase with an EC50 of approximately 1 nM. An MSH binding site characterized in these cells is presumably the MC5 receptor, based on the observation that this is the only other melanocortin receptor mRNA detected in these cells. The MC5 receptor in the 3T3-L1 adipocyte activated adenylyl cyclase in response to alpha-MSH stimulation. Interestingly, Nle4, D-Phe7-alpha-MSH (NDP-MSH), a commonly used synthetic alpha-MSH agonist, was a potent antagonist of the MC5 receptor expressed in the 3T3-L1 cell line. Although the agouti signaling peptide is a potent antagonist of NDP-MSH binding to the MC1 and MC4 melanocortin receptors, agouti was unable to block NDP-MSH binding in the 3T3-L1 adipocyte.
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PMID:Characterization of melanocortin receptor subtype expression in murine adipose tissues and in the 3T3-L1 cell line. 861 46

We expressed epitope-tagged human melanocortin 1 receptor (MC1R) in insect cells using two different recombinant baculovirus constructs; one of which encoded MC1R with an N-terminal Flag epitope and a C-terminal polyHis tag, while the other encoded the MC1R with a C-terminal Myc tag. The constructs were used to infect Sf9 insect cells. For both constructs, immunoblotting with tag-specific antibodies demonstrated the presence of the receptor in the infected cells. The infected Sf9 cells were characterized by radioligand binding using [125I][Nle4,D-Phe7]alpha-MSH. Both saturation and competition analysis, using alpha-, beta-, and gamma 1-MSH on the tagged MC1R expressed in the insect cells, gave binding constants and potency orders that were undistinguishable from those obtained on MC1R expressed in COS cells. The expression level obtained (in the order of pmoles of binding sites per mg of protein) will now facilitate attempts to purify the receptor. This is the first report that demonstrates a functional expression of recombinant melanocortin receptor in nonmammalian cells.
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PMID:Expression of functional melanocortin 1 receptors in insect cells. 863 43

Melanocortin peptides are reported to antagonize opiate dependence and tolerance, but the neural substrates underlying these actions are unknown. In this study, we characterize the rat melanocortin-4 receptor (MC4-R) and demonstrate that this receptor is regulated by opiate administration. The rat MC4-R is 95% identical to the human MC4-R, and the potency of melanocortin peptides to stimulate cAMP production is similar in these two species homologs (alpha-melanocyte-stimulating hormone = adrenocorticotropic hormone > gamma-melanocyte-stimulating hormone). Expression of MC4-R mRNA was found to be enriched in the striatum, nucleus accumbens, and periaque-ductal gray, all of which are regions implicated in the behavioral effects of opiates. In contrast, MC1-, MC3-, and MC5-R are expressed at very low or undetectable levels in these brain regions. Chronic administration of morphine (5 days) resulted in a time-dependent down-regulation of MC4-R mRNA expression in the striatum and periaqueductal gray. Expression of MC4-R mRNA was also decreased in the nucleus accumbens/ olfactory tubercle, but this effect was observed after 1 or 3 days of morphine treatment. In the striatum, the reduction of MC4-R mRNA was accompanied by a concomitant decrease in melanocortin receptor levels, shown by quantitative radioligand binding and autoradiography. In contrast, morphine administration did not influence levels of MC4-R mRNA in several other brain regions, including frontal cortex, olfactory bulb, hypothalamus, and ventral tegmentum/substantia nigra. In light of previous findings that melanocortins antagonize opiate self-administration, analgesic tolerance, and physical dependence, we hypothesize that decreased melanocortin function, via down-regulation of MC4-R expression, may contribute to the development of these opiate-induced behaviors.
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PMID:Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction. 879 97

This study was conducted to determine the binding properties of recently discovered, putative alpha-MSH antagonist 153N-6 peptide at melanocortin receptor subtypes. The results indicated that 153N-6 peptide can competitively inhibit [125I]NDP-MSH binding from all the receptor subtypes investigated. The relative potency order of 153N-6 for inhibiting [125I]NDP-MSH binding was MC1R (Ki 955 +/- 35.7 nM) = MC4R (Ki 1151 +/- 106 nM) > MC3R (Ki 3229 +/- 637 nM) > MC5R (Ki 6286 +/- 462 nM), which is different than the potency order of either NDP-MSH or alpha-MSH. Substitution of aspartic acid117 and histidine260 by alanine in melanocortin 1 receptor resulted in a 4.75-fold decrease (Ki 4541 +/- 644 nM) and an 11-fold increase (Ki 84.29 +/- 4.53 nM), respectively, in the relative potency of 153N-6 for competitively inhibiting [125I]NDP-MSH binding.
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PMID:Characterization of a putative alpha-MSH antagonist 153N-6 at melanocortin receptor subtypes by radioligand binding. 880 44

The DNA encoding the human melanocortin 4 receptor was expressed in COS (CV-1 origin, SV 40) cells and its radioligand binding properties was tested by using the [125I][Nle4, D-Phe7] alpha-melanocyte stimulating hormone (MSH). The radioligand was found to bind to a single saturable site with a Kd of 3.84 +/- 0.57 nmol/l in the MC4 receptor expressing cells. The order of potency of a number of substance competing for the [125I][Nle4, D-Phe7] alpha-MSH binding was the following; [Nle4, D-Phe7] alpha-MSH > [Nle4]-alpha-MSH > beta-MSH > desacetyl-alpha-MSH > alpha-MSH > ACTH (1-39) > ACTH (4-10) > gamma 1-MSH > gamma 2-MSH. This order of potency is unique for the melanocortin 4 receptor when compared to our previously published data for the other melanocortin receptor subtypes. Most notably the melanocortin 4 receptor shows highest affinity for beta-MSH, among the endogenous MSH-peptides. Furthermore the melanocortin 4 receptor shows very low affinity for the gamma-MSH peptides. This distinguishes the melanocortin 4 receptor from the melanocortin 3 receptor, which is the other major central nervous system melanocortin-receptor, as melanocortin 3 receptor shows high affinity for gamma-MSH. Our finding might indicate a specific role for beta-MSH for the melanocortin 4 receptor.
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PMID:Characterisation of the melanocortin 4 receptor by radioligand binding. 888 76

Cyclic alpha-melanocyte-stimulating hormone (alpha-MSH) analogues produced by disulphide bridging (e.g. [Cys4,Cys10] alpha-MSH) are known to be almost equipotent to the native hormone in amphibian skin bioassays and as a consequence have been proposed as a paradigm for the active conformation of native MSH at the pigment cell MC1 receptor. However this proposal has been somewhat speculative as there is no published data comparing biological activity of cyclic MSH analogues with data on receptor binding. This study addresses this problem by comparing tyrosinase stimulatory activity with their receptor binding affinity in B16 murine melanoma cells expressing the native MC1 melanocortin receptor. Cyclic [Cys4,Cys10] alpha-MSH showed almost the same affinity for the MC1 receptor as alpha-MSH, but the linear analogue [Cys4,Cys10] alpha-MSH bound less strongly. Both had biological activities similar to that of the natural ligand. Introduction of D-Phe into the ring in position 7 increased both affinity and activity of the cyclic compound. The study suggests that the intrinsic efficacy of cyclic [Cys4,Cys10] alpha-MSH analogues is similar to native alpha-MSH. Our studies support the proposal that the cyclic structure serves as a good model for the active conformation of linear alpha-MSH.
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PMID:Receptor binding affinities and biological activities of linear and cyclic melanocortins in B16 murine melanoma cells expressing the native MC1 receptor. 893 71

In a previous structure-activity analysis we have shown that the gamma-melanocyte-stimulating hormones (gamma-MSHs) and structurally related adrenocorticotropic hormone (ACTH) fragments share an amino-acid sequence which is determinant for the effects of these peptides on peripheral hemodynamics, viz. a pressor and a tachycardiac response, in conscious rats. We now investigated whether these structural features are also important for the effects of these peptides on cerebral hemodynamics in urethane-anesthetized rats. After intracarotid and intravenous administration, the 'mother' peptides, Lys-gamma2-MSH and gamma2-MSH, and, with a 10-fold lower potency, ACTH-(4-10), caused a dose-dependent pressor and tachycardiac response, as well as an increase in extra- and intracranial blood flow and microcirculatory cerebrocortical blood flow. Removal of C-terminal amino acids resulted in gamma-MSH-fragments which were devoid of effects on peripheral and central hemodynamics. Fragments of gamma2-MSH which were shortened at the N-terminal side (gamma-MSH-(4-12) and gamma-MSH-(5-12)) were less potent than gamma2-MSH, but had an intrinsic activity similar to that of gamma2-MSH with respect to the pressor and tachycardiac effect. However, the potency and intrinsic activity of these shortened fragments on intracerebral hemodynamic parameters were the same as those of gamma2-MSH. This suggests that different mechanisms (e.g., site of action and/or melanocortin receptor subtype) are involved in the cerebral hemodynamic effects of the melanocortins and in their peripheral hemodynamic effects. Surprisingly, removal of an additional residue, His5, resulting in the fragment gamma-MSH-(6-12), led to full restoration of potency with respect to extracranial blood flow, blood pressure and heart rate. Neither the structurally related analog, [Nle4,D-Phe7]alpha-MSH (NDP-MSH), nor ACTH-(1-24) was able to induce a pressor effect or cerebral hemodynamic effects. In contrast, both compounds had a depressor effect. It is concluded that the C-terminal amino acids in the structure of gamma-MSH/ACTH-like peptides are essential for efficacy for the central hemodynamic effects, i.e., the increase in intracerebral (microcirculatory) blood flow. However, in contrast to what holds for the peripheral hemodynamic features, the N-terminal sequence has hardly any influence on potency or efficacy. The results with NDP-MSH and ACTH-(1-24) and the other fragments lead us to postulate that it is not one of the five known subtypes of melanocortin receptors which mediates the hemodynamic effects of the melanocortins, but an additional, still unidentified subtype. A clue for the elucidation of such a receptor might be found in the structural features of gamma-MSH-(6-12) that appear to be very important determinants for the effectiveness to alter peripheral and central hemodynamics.
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PMID:Structure-activity analysis for the effects of gamma-MSH/ACTH-like peptides on cerebral hemodynamics in rats. 901 26

Three-dimensional molecular models of the human melanocortin receptor (hMC1R) have been developed based upon the electron cryo-microscopic structure of bacteriorhodopsin and the electron density footprint of bovine rhodopsin. alpha-Melanocyte-stimulating hormone, Ac-Ser-Tyr-Ser-Met4-Glu-His-Phe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (alpha-MSH, alpha-melanotropin), and the superpotent, prolonged acting agonists, Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (NDP-MSH) and Ac-Nle4-c[Asp5-His6-DPhe7-Arg8-Trp9-Lys10]-NH2 (MTII), have been modeled into the proposed binding sites with specific ligand-receptor interactions identified. The melanotropin sidechain pharmacophores, DPhe7 and Trp9, are proposed to interact with a hydrophobic network of receptor aromatic residues in transmembrane regions 4, 5, 6, and 7. In addition, a hydrophilic network involving the ligand Arg8 and polar receptor residues located in transmembrane regions 2 and 3 were identified. Biological studies on alpha-MSH, NDP-MSH, MTII, and related peptides have been correlated with the proposed hMC1R model in terms of agonism, affinity, and prolongation. Finally, limited MC1R mutagenesis studies comparing alpha-MSH and NDP-MSH are interpreted within the context of the proposed hMC1R models.
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PMID:Three-dimensional molecular models of the hMC1R melanocortin receptor: complexes with melanotropin peptide agonists. 901 63

alpha-Melanocyte-stimulating hormone (alpha-MSH, alpha-melanotropin) and agouti control the switch between eumelanin and pheomelanin synthesis in mammalian melanocytes. Here we investigated interactions between alpha-MSH, agouti protein, cAMP elevating agents and phorbol ester on mouse B16 melanoma cells. Agouti (Kd 3.7 nmol/l) and alpha-MSH (Kd 2.3 nmol/l) had similar affinities to the MC1 melanocortin receptor. Both alpha-MSH and agouti induced MC1 receptor down-regulation. Agouti antagonized melanogenesis induced by alpha-MSH, forskolin, cholera toxin (CT), and pertussis toxin (PT). It also reduced the constitutive melanin formation of long-term cultures. Cell proliferation was inhibited by agouti (43% at 100 nM). This effect was reversed by alpha-MSH, forskolin, or CT. B16-G4F cells, a cell variant that lacks the MC1 receptor, did not respond to agouti. From these results we conclude that agouti shows the characteristics of an inverse agonist acting through the MC1 receptor.
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PMID:Interactions of alpha-melanotropin and agouti on B16 melanoma cells: evidence for inverse agonism of agouti. 902 82


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