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)

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

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

alpha-Melanocyte-stimulating hormone (alpha-MSH, alpha-melanotropin) has been shown to be an inhibitory factor in many immunologic and inflammatory processes involving the cytokine interleukin-1 (IL-1). As the mechanism of the interaction between IL-1 and alpha-MSH at the receptor level is unknown, we have studied the role of MC1 melanocortin receptors in two variants of the human melanoma cell line A375 differing in their sensitivity to the cytostatic effects of IL-1 beta. Both IL-1 sensitive (A375r-) and resistant cells (A375r+) carry specific high affinity receptors for IL-1, albeit their concentration is 10-fold higher in A375r+ cells. In A375r- cells, MC1 receptors are absent or below the level for reliable detection in the binding assay. Conversion of A375r- to A375r+ cells by prolonged culture in medium not depleted of endotoxin led to the appearance of MC1 receptors (KD 0.4 +/- 0.123 nmol/l; 608 +/- 134 receptors/cell). Stable transfection of A375r- cells with the human MC1 receptor did not, however, render them resistant to the cytostatic effect of IL-1 beta on concomitant treatment with alpha-MSH or result in the production of IL-6 on treatment with IL-1 beta. Therefore, the presence of MC1 receptors on the surface of A375 cells or their binding to alpha-MSH does not seem to be a factor in cytokine resistance or IL-6 secretion. No interaction between IL-1 beta and alpha-MSH could be demonstrated at the cellular level in this melanoma cell line.
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PMID:MSH receptors and the response of human A375 melanoma cells to interleukin-1 beta. 902 91

We have previously reported that melatonin was an effective lightening agonist in the teleost Synbranchus marmoratus, the amphibians Rana pipiens and Bufo ictericus, and in the lizard Anolis carolinensis. The hormone, previously applied to the preparations, effectively inhibited alpha-MSH darkening activity in a dose-independent manner, and was also able to reverse MSH-induced darkening. We presently describe the inhibitory effect of the indoleamine on the murine melanoma cell proliferation. Interestingly, the hormone also stimulated tyrosinase activity, with a correlated increase in melanin content. We also demonstrate that in a diverse lizard species, Urosaurus ornatus, the indoleamine was totally ineffective. The competitive MSH antagonistic activity of H-His-D-Arg-Ala-Trp-D-Phe-Lys-NH2 has been demonstrated previously in R. pipiens and U. ornatus. Herein, its inhibitory activity is also reported in another lizard species, A. carolinensis. However, this MSH analogue was inactive in S. marmoratus, and in murine melanoma cells. On the other hand, the 7 thru 10 alpha-MSH fragment, Ac-Phe-Arg-Trp-Gly-NH2, although ineffective in S. marmoratus and R. pipiens, was an alpha-MSH antagonist in A. carolinensis. Surprisingly, in the melanoma cell line, the MSH fragment exhibited no agonist or antagonist activity, but dramatically potentiated the MSH-induced increase in tyrosinase activity. These data might suggest that the fragment is participating either in the process of facilitation or in positive cooperativity. The present results, taken together with our previously reported data, demonstrate a major interspecies diversity of the MC1 subtype of melanocortin receptor, and point out the relevance of the membrane microenvironment for the final receptor configuration.
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PMID:Comparative biological activities of alpha-MSH antagonists in vertebrate pigment cells. 907 3

1. We investigated the effects of [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH), adrenocorticotropin-(1-24) (ACTH-(1-24)) and gamma 2-MSH, three melanocortins with different agonist selectivity for the five cloned melanocortin receptors, on blood pressure and heart rate in conscious, freely moving rats following intravenous administration. 2. As was previously found by other investigators as well as by us gamma 2-MSH, a peptide suggested to be an agonist with selectivity for the melanocortin MC3 receptor, caused a dose-dependent, short lasting pressor response in combination with a tachycardia. Despite the fact that NDP-MSH is a potent agonist of various melanocortin receptor subtypes, among which the melanocortin MC1 receptor, it did not affect blood pressure or heart rate, when administered i.v. in doses of up to 1000 nmol kg-1. 3. ACTH-(1-24) caused a dose-dependent decrease in blood pressure in combination with a dose-dependent increase in heart rate in a dose-range from 15 to 500 nmol kg-1. The cardiovascular effects of ACTH-(1-24) were independent of the presence of the adrenals. 4. Pretreatment with ACTH-(1-24) caused a pronounced, dose-dependent parallel shift to the right of the dose-response curve for the pressor and tachycardiac effects of gamma 2-MSH. The antagonistic effect of ACTH-(1-24) was already apparent following a dose of this peptide as low as 10 nmol kg-1, which when given alone had no intrinsic hypotensive activity. 5. These results form further support for the notion that it is not via activation of one of the as yet cloned melanocortin receptors that gamma-MSH-like peptides increase blood pressure and heart rate. The cardiovascular effects of ACTH-(1-24) seem not to be mediated by the adrenal melanocortin MC3 receptors, for which ACTH-(1-24) is a selective agonist, or by adrenal catecholamines. 6. There appears to be a functional antagonism between ACTH-(1-24) and gamma 2-MSH, two melanocortins derived from a common precursor, with respect to their effect on blood pressure and heart rate. Whether this antagonism plays a (patho)physiological role remains to be shown.
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PMID:Different cardiovascular profiles of three melanocortins in conscious rats; evidence for antagonism between gamma 2-MSH and ACTH-(1-24). 911 79

Dominant mutations at the agouti locus induce several phenotypic changes in the mouse including yellow pigmentation (phaeomelanization) of the coat and adult-onset obesity. Nonpigmentary phenotypic changes associated with the agouti locus are due to ectopic expression of the agouti-signaling protein (ASP), and the pheomelanizing effects on coat color are due to ASP antagonism of alpha-MSH binding to the melanocyte MC1 receptor. Recently it has been demonstrated that pharmacological antagonism of hypothalamic melanocortin receptors or genetic deletion of the melanocortin 4 receptor (MC4-R) recapitulates aspects of the agouti obesity syndrome, thus establishing that chronic disruption of central melanocortinergic signaling is the cause of agouti-induced obesity. To learn more about potential downstream effectors involved in these melanocortinergic obesity syndromes, we have examined expression of the orexigenic peptides galanin and neuropeptide Y (NPY), as well as the anorexigenic POMC in lethal yellow (A(y)), MC4-R knockout (MC4-RKO), and leptin-deficient (ob/ob) mice. No significant changes in galanin or POMC gene expression were seen in any of the obese models. In situ hybridizations using an antisense NPY probe demonstrated that in obese A(y) mice, arcuate nucleus NPY mRNA levels were equivalent to that of their C57BL/6J littermates. However, NPY was expressed at high levels in a new site, the dorsal medial hypothalamic nucleus (DMH). Expression of NPY in the DMH was also seen in obese MC4-RKO homozygous (-/-) mice, but not in lean heterozygous (+/-) or wild type (+/+) control mice. This identifies the DMH as a brain region that is functionally altered by the disruption of melanocortinergic signaling and suggests that this nucleus, possibly via elevated NPY expression, may have an etiological role in the melanocortinergic obesity syndrome.
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PMID:Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the agouti obesity syndrome. 913 6

Five subtypes of melanocortin receptors have to date been identified, but to date little is known about the different structural requirements for binding and biological activity at these receptors. In this study, the role of C-terminal melanocortin peptide residues in imparting selectivity for the receptor subtypes was examined. C-terminally modified analogues of alpha-MSH and gamma-MSH were synthesized and their interaction with MC1 and MC3 melanocortin receptors was investigated. This study provides further evidence for an important role of proline 12 (numbering with respect to alpha-MSH) for binding and activity at the MC1 receptor. Although the influence of C-terminal amino acids on binding and activity at MC3-R was less marked, some of them were nevertheless observed to be beneficial for the interaction with this receptor subtype.
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PMID:Binding and biological activity of C-terminally modified melanocortin peptides: a comparison between their actions at rodent MC1 and MC3 receptors. 935 58

The binding of the 2 cyclic lactam MSH (4-10) analogues (MTII, SHU9119), and 5 cyclic [Cys4, Cys10] alpha-MSH analogues were tested on cells transiently expressing the human MC1, MC3, MC4 and MC5 receptors. The results indicate a differential importance of the C-terminal (Lys-Pro-Val) and N-terminal (Ser-Tyr-Ser) of cyclic [Cys4, Cys10] alpha-MSH analogues in binding to the MC receptor subtypes. Substitution of D-Phe7 by D-Nal(2')7 in both the cyclic lactam MSH (4-10) and the cyclic disulphide MSH (4-10) analogues resulted in a shift in favour of selectivity for the MC4 receptor; the disulphide analogue, [Cys4, D-Nal(2')7 Cys10] alpha-MSH (4-10) (HS9510), showing the highest selectivity for the MC4 receptor among all the substances tested. However, the cyclic lactams displayed an over all higher affinity for the MC receptors, than any of the cyclic disulphide MSH (4-10) analogues.
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PMID:Selectivity of cyclic [D-Nal7] and [D-Phe7] substituted MSH analogues for the melanocortin receptor subtypes. 935 59

Melanocytes synthesise two types of melanin: the brown-black eumelanin and the red-yellow phaeomelanin. In mice, the relative proportions of these two melanins are regulated by alpha-MSH, which preferentially increases the synthesis of eumelanin and by the Agouti protein (AP), the expression of which correlates with the growth of yellow phaeomelanin-containing hair. It has been proposed that AP acts by antagonizing the action of alpha-MSH at the MC1 receptor, although it has been suggested that it may also act independently of alpha-MSH. In the present study we show that AP inhibits melanogenesis in B16F1 melanoma cells in the presence and absence of alpha-MSH and also causes dose-related decreases in the synthesis of both eumelanin and phaeomelanin. In the presence of alpha-MSH AP had a greater effect on eumelanin production and this is consistent with an antagonistic action at the MC1 receptor. In the absence of alpha-MSH however, AP produced similar reductions in the synthesis of both melanins. These changes were not seen in B16G4F cells which lack the MC1 receptor, suggesting that even in the absence of alpha-MSH AP acts at the MC1 receptor. How this action is mediated at the intracellular level is not yet clear, although it appears to be associated with a decrease in tyrosinase activity.
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PMID:Agouti protein inhibits the production of eumelanin and phaeomelanin in the presence and absence of alpha-melanocyte stimulating hormone. 935 25

ACTH(1-39), and several shorter N- and/or C-terminally truncated fragments of ACTH, with and without N-terminal acetylation and/or C-terminal amidation, were tested for binding on a single eukaryotic cell line transiently and independently expressing the melanocortin MC1, MC3, MC4 and MC5 receptors. The results show that none of these MC receptors has specific binding epitopes for the ACTH peptides beyond the amino acid sequence of alpha-MSH, when tested for their ability to compete with 125I-labelled [Nle4,D-Phe7]alpha-MSH and ACTH. The MC3 receptor favours the natural desacetylated N-terminal end of the ACTH peptides, and it has generally more than 10-fold higher affinity for the ACTH peptides than the MC4 receptor. Considering earlier anatomical localisation data, together with the present data, we suggest that the MC3 receptor is the most likely candidate of the MC receptors to mediate the short-loop negative feedback release of corticotrophin-releasing factor (CRF) caused by ACTH/MSH peptides.
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PMID:The melanocortin 1, 3, 4 or 5 receptors do not have a binding epitope for ACTH beyond the sequence of alpha-MSH. 939 8


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