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) is an agonist, and agouti-related protein (Agrp) an endogenous antagonist at the melanocortin 3 and 4 receptors which are found in the central nervous system (CNS). We have examined the effect of alpha-MSH and Agrp on the hypothalamo-pituitary-adrenal (HPA) axis in vitro and in vivo in male rats. Intraparaventricular nuclear (iPVN) injection of [Nle(4),D-Phe(7)]-alpha-MSH (NDP-MSH) (a long-acting alpha-MSH analogue) increased plasma adrenocorticotropic hormone (ACTH) (10 min post-injection: 25.0 +/- 3.9 vs. saline 10.9 +/- 2.0, p < 0.05) and plasma corticosterone (10 min post-injection: 174.1 +/- 14.2 vs. saline 124.7 +/- 16.3 ng/ml, p < 0.05). iPVN injection of Agrp(83-132) increased plasma ACTH (24.2 +/- 4.0 vs. saline 10.1 +/- 1.0 pg/ml, p < 0.01). The combination of NDP-MSH and Agrp(83-132) administered iPVN significantly increased plasma ACTH (10 min post-injection: 21.3 +/- 3.8 vs. 10.9 +/- 2.0, p < 0.05) and plasma corticosterone (10 min post-injection: 169.0 +/- 15.1 vs. saline 124.7 +/- 16.3 ng/ml, p < 0.05), but there was no additive effect. Hypothalamic explants treated with alpha-MSH (100 nM) resulted in a 159 +/- 23% increase in corticotropin-releasing hormone (CRH) release (p < 0.01) and 175 +/- 12% increase in arginine vasopressin (AVP) release (p < 0.001) compared to basal. Agrp(83-132) (100 nM) administered to hypothalamic explants resulted in a 161 +/- 20% increase in CRH (p < 0.01) and 174 +/- 13% increase in AVP release (p < 0.001) compared to basal. Hypothalamic explants treated with the combination of alpha-MSH and Agrp(83-132) (100 nM) resulted in a 179 +/- 31% increase in CRH release (p < 0.01) and 130 +/- 9% increase in AVP release (p < 0.01) compared to basal, but there was no additive effect. This is the first report that both alpha-MSH and Agrp(83-132) stimulate the HPA axis. The combination of alpha-MSH and Agrp(83-132) has no additive effect in vitro and in vivo in male rats. These results suggest that there may be another receptor independent of the known melanocortin receptors at which Agrp is acting.
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PMID:The hypothalamic melanocortin system stimulates the hypothalamo-pituitary-adrenal axis in vitro and in vivo in male rats. 1197 51

The melanocortin 3 and 4 receptors are G-protein-coupled receptors found in the hypothalamus with important role in regulation of the energy balance. In this study, we performed pharmacological comparison of the rat and human melancortin (MC) 3 and MC4 receptors. We transiently expressed the genes for these receptors individually in a mammalian cell line and determined the binding affinities to several MSH peptides. The results showed no major difference between the rat and human MC3 receptors while the rat MC4 receptor had higher affinity to several peptides compared with the human MC4 receptor. NDP-, alpha-, beta-, gamma-MSH, ACTH(1-24), HS014 and MTII had from 5- to 34-fold higher affinity for the rat MC4 receptor, while SHU9119, HS024 and HS028 had similar affinity for both the MC4 receptors. Pharmacological species difference have earlier been reported for the MC1 and MC5 receptors but this is the first report showing important differences between the rat and human MC4 receptors.
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PMID:Pharmacological comparison of rat and human melanocortin 3 and 4 receptors in vitro. 1204 4

A number of neuropeptides implicated in the hypothalamic regulation of appetite are synthesized in the arcuate nucleus (Arc). Neuropeptide Y (NPY) and agouti-related protein (Agrp) are orexigenic. The pro-opiomelanocortin (POMC) product alpha-melanocyte-stimulating hormone (alpha-MSH) is anorectic. Intracerebroventricular administration of cocaine- and amphetamine-regulated transcript (CART) decreases food intake. However, recent results show that CART is orexigenic when injected into discrete hypothalamic nuclei. There is almost complete coexpression of NPY and Agrp mRNA in Arc neurones, and the majority of CART-containing neurones in the Arc also contain POMC mRNA. We investigated possible interactions between these neuropeptides in vitro using a rat hypothalamic explant system. Administration of 1, 10 and 100 nm of NPY to hypothalamic explants significantly increased release of Agrp(83-132)-immunoreactivity (IR). NPY (10 and 100 nm) significantly increased the release of CART(55-102)-IR and alpha-MSH-IR from hypothalamic explants. Agrp(83-132) (10 nm) administered to hypothalamic explants significantly increased the release of NPY-IR. Agrp(83-132) (10 and 100 nm) significantly decreased the release of CART(55-102)-IR from hypothalamic explants. Administration of 1, 10 and 100 nm CART(55-102) to hypothalamic explants resulted in a significant increase in NPY-IR release. Administration of 10 nm CART(55-102) to hypothalamic explants significantly increased the release of Agrp(83-132)-IR. NDP-MSH (10 nm) administered to hypothalamic explants significantly increased the release of NPY-IR. NDP-MSH (10 and 100 nm) significantly increased the release of Agrp(83-132)-IR from hypothalamic explants. These data suggest that orexigenic neuropeptides in the arcuate nucleus stimulate the release of each other, perhaps reinforcing orexigenic behaviour via a positive-feedback loop. Our results are also in keeping with the possibility that the melanocortin-3 receptor in the arcuate nucleus may influence the release of arcuate neuropeptides.
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PMID:Hypothalamic interactions between neuropeptide Y, agouti-related protein, cocaine- and amphetamine-regulated transcript and alpha-melanocyte-stimulating hormone in vitro in male rats. 1221 33

Loss-of-function mutations in the human melanocortin-4 receptor (MC4R) are associated with obesity. Previous work has implicated a C-terminal di-isoleucine motif at residues 316/317 in MC4R cell surface targeting. It was therefore of interest to examine function and cell surface expression of an MC4R mutation found in an obese proband in which one of these isoleucines was substituted by threonine (I317T). Single mutant (I316T or I317T) and double mutant (I316T,I317T) forms of MC4R were constructed by oligonucleotide-directed mutagenesis and tested for function and cell surface expression in transfected cells. Function was assessed using assays for agonist, [Nle(4)-d-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) or forskolin-stimulated cAMP accumulation. Cell surface expression was determined by whole-cell binding of [(125)I]NDP-alpha-MSH, fluorescence immunocytochemistry and fluorescence-activated cell sorting. Maximal cAMP generation of the single mutants was reduced by 40% of wild-type receptor; the double mutant further reduced function to 40% of control, effects that were mirrored by decreases in cell-surface expression. Quantitative RT-PCR showed that, relative to wild-type receptor, transcript levels for the mutated receptors were not reduced. The results further implicate the C-terminal di-isoleucines in cell surface expression of MC4R and suggest that mutations of residues 316 or 317 would predict MC4R hypofunction.
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PMID:Cell surface expression of the melanocortin-4 receptor is dependent on a C-terminal di-isoleucine sequence at codons 316/317. 1259 26

Seven alleles of the chicken melanocortin (MC) 1 receptor were cloned into expression vectors, expressed in mammalian cells and pharmacologically characterized. Four of the clones e(+R), e(+B&D), e(wh)/e(y), E(Rfayoumi) gave receptors to which melanocortin stimulating hormone (alpha-MSH) and NDP-MSH bound with similar IC50 values and responded to alpha-MSH by increasing intracellular cAMP levels in a dose-dependent manner. Three of the cMC1 receptors; e(b), E and E(R), did not show any specific binding to the radioligand, but were found to be constitutively active in the cAMP assay. The E and E(R) alleles are associated with black feather colour in chicken while the eb allele gives rise to brownish pigmentation. The three constitutively active receptors share a mutation of Glu to Lys in position 92. This mutation was previously found in darkly pigmented sombre mice, but constitutively active MC receptors have not previously been shown in any nonmammalian species. We also inserted the Glu to Lys mutation in the human MC1 and MC4 receptors. In contrast with the chicken clones, the hMC1-E94K receptor bound to the ligand, but was still constitutively active independently of ligand concentration. The hMC4-E100K receptor did not bind to the MSH ligand and was not constitutively active. The results indicate that the structural requirements that allow the receptor to adapt an active conformation without binding to a ligand, as a consequence of this E/K mutation, are not conserved within the MC receptors. The results are discussed in relationship to feather colour in chicken, molecular receptor structures and evolution. We suggest that properties for the 'E92K switch' mechanism may have evolved in an ancestor common to chicken and mammals and were maintained over long time periods through evolutionary pressure, probably on closely linked structural features.
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PMID:Association of feather colour with constitutively active melanocortin 1 receptors in chicken. 1265 99

Among the melanocortins alpha-MSH is known to be involved in feeding behavior. These hormones mediate their effects through G protein-coupled receptors by stimulating adenylate cyclase. In this study, we have developed an in vitro expression model for human melanocortin 3 receptor (hMC3R) tagged at its C terminus with EGFP. The corresponding chimeric cDNA was stably expressed in HEK293 cells. The selected clones expressing the hMC3R-EGFP exhibited cell surface fluorescence and responded to NDP-MSH stimulation by producing cAMP in a dose-dependent manner (EC(50): 0.3 nM). Binding studies revealed a single class of binding sites with a K(D) of 2.24 nM. Moreover, Agouti-related protein was also demonstrated to be an antagonist of the hMC3R-EGFP. Thus, the hMC3R tagged with EGFP stably expressed in HEK293 cells, exhibiting the same characteristics than the wild-type hMC3R, is the only model of expression of this receptor allowing its direct localization inside living cells.
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PMID:Stable expression of human melanocortin 3 receptor fused to EGFP in the HEK293 cells. 1278 89

Previous animal studies have demonstrated that alpha-melanocyte-stimulating hormone (alpha-MSH) is a sebotropic hormone in rats and that targeted disruption of melanocortin 5 receptor (MC5-R) can down-regulate sebum output in mice. To study the role of proopiomelanocortin (POMC) peptides in the regulation of human sebaceous lipid production and sebocyte differentiation, we established a primary human sebocyte culture system. Sebocytes were derived from normal human facial skin. Differentiation of sebocytes, induced by POMC-derived peptides such as MSH, adrenocorticotropic hormone (ACTH), or bovine pituitary extract (BPE), resulted in the appearance of prominent cytoplasmic lipid droplets. Partial induction of sebocyte differentiation also was observed in serum-depleted cultures, but there was very limited spontaneous differentiation in serum-containing medium. Analysis by high-performance thin-layer chromatography (HPTLC) of (14)C-acetate-labeled lipids showed a dose-dependent increase in synthesis of sebaceous-specific lipid (i.e., squalene) induced by NDP alpha-MSH. Molecular studies using RT-PCR showed a low level of human MC5-R expression under serum-free condition but a substantial increase after treatment with NDP alpha-MSH or BPE. In contrast, MC1-R expression remained the same, independent of treatment. Our data indicate that expression of MC5-R correlates with sebocyte differentiation and suggest a regulatory role for MC5-R in human sebaceous lipid production.
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PMID:Proopiomelanocortin peptides and sebogenesis. 1285 11

Scintigraphic imaging of metastatic melanoma lesions requires highly tumor-specific radiopharmaceuticals. Because both melanotic and amelanotic melanomas overexpress melanocortin-1 receptors (MC1R), radiolabeled analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) are potential candidates for melanoma diagnosis. Here, we report the in vivo performance of a newly designed octapeptide analogue, [betaAla(3), Nle(4), Asp(5), D-Phe(7), Lys(10)]-alpha-MSH(3-10) (MSH(OCT)), which was conjugated through its N-terminal amino group to the metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to enable incorporation of radiometals (e.g., indium-111) into the peptide. DOTA-MSH(OCT) displayed high in vitro MC1R affinity (IC(50) 9.21 nM). In vivo [(111)In]DOTA-MSH(OCT) exhibited a favorable biodistribution profile after injection in B16-F1 tumorbearing mice. The radiopeptide was rapidly cleared from blood through the kidneys and, most importantly, accumulated preferentially in the melanoma lesions. Lung and liver melanoma metastases could be clearly imaged on tissue section autoradiographs 4 h after injection of [(111)In]DOTA-MSH(OCT). A comparative study of [(111)In]DOTA-MSH(OCT) with [(111)In]DOTA-[Nle(4), D-Phe(7)]-alpha-MSH ([(111)In]-DOTA-NDP-MSH) demonstrated the superiority of the DOTA-MSH(OCT) peptide, particularly for the amount of radioactivity taken up by nonmalignant organs, including bone, the most radiosensitive tissue. These results demonstrate that [(111)In]DOTA-MSH(OCT) is a promising melanoma imaging agent.
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PMID:DOTA alpha-melanocyte-stimulating hormone analogues for imaging metastatic melanoma lesions. 1285 39

Posttranscriptional processing of proopiomelanocortin (POMC) yields melanocortin peptides, which are involved in the regulation of energy balance in mammals. The sequence preservation of the main brain melanocortin, alpha-melanocyte-stimulating hormone (alpha-MSH), suggests a conserved function throughout vertebrate evolution. We studied the involvement of the central melanocortin system in the control of food intake in the goldfish. In situ hybridization studies done following molecular cloning of POMC mRNA demonstrated positive POMC mRNA cell bodies exclusively expressed within the mediobasal hypothalamus, in the anterior, posterior and inferior part of the lateral tuberal nucleus and the medial region of the lateral recess nucleus. POMC expression is localized in brain areas appropriate for involvement in food intake and neuroendocrine regulation. Progressive fasting did not affect POMC mRNA expression levels. Intracerebroventricular administration of [Nle(4), D-Phe(7)]-alpha-MSH (NDP-alpha-MSH), a universal melanocortin agonist, within nanomolar range, dose-dependently inhibited food intake 2 h after treatment. The results show for the first time a functional melanocortin system in fishes that participates in central regulation of food intake. The conserved central expression pattern of POMC mRNA and role of MSH peptides in physiological regulation of food intake suggests that melanocortin functions were gained early in vertebrate evolution.
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PMID:The central melanocortin system regulates food intake in goldfish. 1297 25

Following the first synthesis of tritiated alpha-melanocyte-stimulating hormone (alpha-MSH, alpha-melanotropin) in 1974 by Medzihradszky et al., several alpha-MSH analogs were designed containing between 2 and 12 tritium atoms, the latter of which displayed a specific radioactivity of 12.21 GBq/micromol (330 Ci/mmol). Similarly, radioiodinated alpha-MSH analogs of high purity, full biological activity and a specific radioactivity of approximately 140 GBq/micromol were obtained. Although tritiated and radioiodinated alpha-MSH became indispensable tools as tracer molecules for numerous in vitro and in vivo studies, above all for receptor identification and characterization as well as for structure-activity studies, they did not fulfill the criteria required for therapeutic in vivo targeting of metastatic melanoma. Therefore, we recently developed alpha-MSH analogs containing the universal metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) in different positions of the molecule. As DOTA can equally well incorporate diagnostic (e.g. (111)In, (67,68)Ga) and therapeutic (e.g. (90)Y, (67)Cu) radionuclides, DOTA-MSH compounds may serve for both melanoma scintigraphy and therapy. The analog DOTA-[betaAla(3), Nle(4), Asp(5), D-Phe(7), Lys(10)]-alpha-MSH(3-10) (DOTA-MSH(OCT)), which contains the metal chelator at its N-terminal end, displayed good in vitro MC1R affinity (IC(50) 9.21 nm). In vivo, [(111)In]DOTA-MSH(OCT) exhibited a favorable biodistribution profile after injection in B16-F1 tumor-bearing mice. The radiopeptide was rapidly cleared from blood through the kidneys and, most importantly, accumulated preferentially in the melanoma lesions. Lung and liver melanoma metastases could be clearly imaged on tissue section autoradiographs 4 h after injection of [(111)In]DOTA-MSH(OCT). A comparative study of [(111)In]DOTA-MSH(OCT) with [(111)In]DOTA-[Nle(4), D-Phe(7)]-alpha-MSH ([(111)In]DOTA-NDP-MSH) demonstrated the superiority of the DOTA-MSH(OCT) peptide, particularly with respect to the amount of radioactivity taken up by non-malignant organs, including bone, the most radiosensitive tissue. These results demonstrate that [(111)In]DOTA-MSH(OCT) specifically targets melanoma metastases and represents a lead compound for the development of therapeutic DOTA-MSH analogs.
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PMID:Radiolabeled alpha-melanocyte-stimulating hormone analogs for receptor-mediated targeting of melanoma: from tritium to indium. 1452 36


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