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

alpha, beta, gamma-MSH and ACTH are derived from the same precursor, POMC(proopiomelanocortin), and are classified as melanocortin. alpha-MSH plays an important role in the regulation of appetite and energy expenditure via central melanocortin receptor, melanocortin 4 receptor(MC4R), which is expressed mainly in hypothalamus. alpha-MSH or its analogue shows inhibitory effect on appetite and inversely MC4R antagonist stimulates appetite. MC4R knock-out mice has adult-onset obesity and decreased energy expenditure. POMC gene expression in hypothalamus is partially regulated by leptin. Agouti-related peptide(AgRP), a homologue of agouti peptide and antagonist of MC3R and MC4R, is expressed in human brain and may act as a inhibitor of alpha-MSH. From the genetical aspect, the region near POMC gene, 2p23, is one of the susceptibility loci of human obesity. POMC gene mutations are found in two families, where mutations in both alleles cause human obesity, red hair, adrenal dysfunction, due to alpha-MSH and ACTH deficiencies. In morbidity obese patients, heterozygous MC4R gene mutations are found among 4% of them. These results suggest the importance of melanocortin and its receptors on appetite regulation in human.
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PMID:[Regulation of appetite by melanocortin and its receptors]. 1126 89

Recently, leptin was cloned and characterized as a sateity factor which acts through the hypothalamus. alpha-melanocyte-stimulating hormone derived from pro-opiomelanocortin(POMC) and melanocortin receptor-4(MC4-R) have been reported to be involved in the downstream of the effect of leptin. In this paper, we summarized the clinical characteristics and the mechanisms of obesity caused by genetic abnormalities involved in the regulatory mechanism of appetite such as leptin, leptin receptor, POMC, MC4-R and prohormone convertase 1.
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PMID:[Genetic abnormalities of regulatory mechanism of appetite]. 1126 92

Cerulenin and a related compound, C75, have recently been reported to reduce food intake and body weight independent of leptin through a mechanism hypothesized, like leptin, to involve hypothalamic nutrition-sensitive neurons. To assess whether these inhibitors act through mechanisms similar to mechanisms engaged by leptin, ob/ob and Ay (agouti) mice, as well as fed and fasted wild-type mice, were treated with cerulenin. Like leptin, cerulenin reduced body weight and food intake and increased metabolic rate in ob/ob mice, and cerulenin produced the same effects in wild-type mice, whereas lithium chloride, at doses that produce conditioned taste aversion, reduced metabolic rate. However, in contrast to leptin, cerulenin did not prevent effects of fasting on plasma corticosterone or hypothalamic levels of neuropeptide Y, agouti-related peptide, pro-opiomelanocortin, or cocaine- and amphetamine-related peptide mRNA. Also, in contrast to leptin, cerulenin was highly effective to reduce body weight in Ay mice, in which obesity is caused by blockade of the melanocortin receptor. These data demonstrate that cerulenin produces metabolic effects similar to effects of leptin, but through mechanisms that are independent of, or down-stream from, both leptin and melanocortin receptors.
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PMID:Cerulenin mimics effects of leptin on metabolic rate, food intake, and body weight independent of the melanocortin system, but unlike leptin, cerulenin fails to block neuroendocrine effects of fasting. 1128 36

In vitro mutagenesis of the mouse melanocortin-4 receptor (mMC4R) has been performed, based upon homology molecular modeling and previous melanocortin receptor mutagenesis studies that identified putative ligand-receptor interactions. Twenty-three mMC4 receptor mutants were generated and pharmacologically characterized using several melanocortin-based ligands [alpha-MSH, NDP-MSH, MTII, DNal (1')(7)-MTII, Nal(2')(7)-MTII, SHU9119, and SHU9005]. Selected mutant receptors possessing significant differences in the melanocortin-based peptide agonist and/or antagonist pharmacology were further evaluated using the endogenous antagonist agouti-related protein fragment hAGRP(83-132) and hAGRP(109-118) molecules. These studies of the mouse MC4R provide further experimental data suggesting that the conserved melanocortin receptor residues Glu92 (TM2), Asp114 (TM3), and Asp118 (TM3) (mouse MC4R numbering) are important for melanocortin-based peptide molecular recognition. Additionally, the Glu92 and Asp118 mMC4R residues are important for molecular recognition and binding of AGRP(83-132). We have identified the Phe176 (TM4), Tyr179 (TM4), Phe254 (TM6), and Phe259 (TM6) receptor residues as putatively interacting with the melanocortin-based ligand Phe(7) by differences between alpha-MSH and NDP-MSH agonist potencies. The Glu92, Asp118, and Phe253 mMC4R receptor residues appear to be critical for hAGRP(83-132) molecular recognition and binding while Phe176 appears to be important for functional antagonism of AGRP(83-132) and AGRP(109-118) but not molecular recognition. The Phe253 mMC4R residue appears to be important for AGRP(83-132) molecular recognition and general mMC4 receptor stimulation. The Phe254 and Phe259 mMC4R amino acids may participate in the differentiation of agonist versus antagonist activity of the melanocortin-based peptide antagonists SHU9119 and SHU9005, but not AGRP(83-132) or AGRP(109-118). The Met192 side chain when mutated to a Phe results in a constitutively active mMC4R that does not effect agonist ligand binding or potency. Melanocortin-based peptides modified at the 7 position of MTII with DPhe, DNal(1'), Nal(2'), and DNal(2') have been pharmacologically characterized at these mutant mouse MC4Rs. These data suggest a revised hypothesis for the mechanism of SHU9119 antagonism at the MC4R which may be attributed to the presence of a "bulky" naphthyl moiety at the 7 position (original hypothesis), and additionally that both the stereochemistry and naphthyl ring position (2' versus 1') are important for positioning of the ligand Arg(8) residue with the corresponding mMC4R amino acids.
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PMID:Structure activity studies of the melanocortin-4 receptor by in vitro mutagenesis: identification of agouti-related protein (AGRP), melanocortin agonist and synthetic peptide antagonist interaction determinants. 1135 54

The pro-opiomelanocortin-derived peptides and the melanocortin receptors are implicated in various functions within the CNS including the regulation of food intake. In the present study, we used in situ hybridization, with specific 35S-labelled ovine riboprobes to map the expression of melanocortin receptor-3 (MC3-R) and -4 (MC4-R) mRNA in the diencephalon and brainstem of normal female sheep. Furthermore, we examined the effect of long-term alterations in energy balance on the distribution and expression of MC3-R and MC4-R mRNA in food-restricted and ad libitum-fed ovariectomized female sheep. The distribution of melanocortin receptors generally resembled that of the rat. A high number of MC3-R-labelled cells were seen in the ventral division of the lateral septum and the medial preoptic area. In the hypothalamus, a moderate number of MC3-R-labelled cells was observed in the lateral hypothalamic area while other nuclear groups had low to intermediate numbers of MC3-R-labelled cells. The distribution of MC4-R mRNA was generally similar to that of MC3-R mRNA in the septal/preoptic and hypothalamic regions, with a high number of labelled cells present in the intermediate division of the lateral septum. Within the hypothalamus, no MC4-R mRNA expression was observed in the arcuate nucleus. There was more widespread distribution of moderate to low numbers of MC4-R mRNA-expressing cells in the brainstem compared to that of MC3-R mRNA. Unlike findings in the rat, only a low number of cells expressed melanocortin receptor mRNA in the ovine hypothalamic nuclei associated with feeding behavior. The number of melanocortin receptor-labelled cells and the level of expression (silver grains/cell) in the hypothalamic feeding centers was similar in food-restricted and ad libitum-fed animals. These findings suggest that long-term alterations in metabolic status do not change the melanocortin receptor mRNA distribution and/or expression in the sheep hypothalamus.
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PMID:Long-term alterations in body weight do not affect the expression of melanocortin receptor-3 and -4 mRNA in the ovine hypothalamus. 1153 Feb 31

Energy balance and insulin action are tightly coregulated. Leptin regulates energy intake and expenditure partly by modulation of the melanocortin pathway in the hypothalamus. Here we demonstrate potent effects of the melanocortin pathway on insulin action and body distribution of adiposity. Conscious rats received week-long infusions of either a melanocortin receptor agonist, alpha-melanocyte-stimulating hormone (alpha-MSH), or antagonist, SHU9119, in the third cerebral ventricle while food intake was maintained constant in each group. alpha-MSH decreased intra-abdominal fat and markedly enhanced the actions of insulin on both glucose uptake and production, while SHU9119 exerted opposite effects. Our findings elucidate a neuroendocrine network that is likely to play a central role in the coupling of energy intake and insulin action.
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PMID:Central melanocortin receptors regulate insulin action. 1158 Dec 96

In humans, damage to the nervous system can lead to a pain state referred to as neuropathic pain. Here, we give a short overview of the clinical picture and classification of neuropathic pain and highlight some of the currently known pathophysiological mechanisms involved, with special emphasis on neuropeptide plasticity. In this context, we discuss a specific group of neuropeptides, the melanocortins. These peptides have been demonstrated to play a role in nociception and to functionally interact with the opiate system. Recently, we demonstrated that spinal melanocortin receptors are upregulated in a rat model of neuropathic pain and that blockade of the melanocortin MC(4) receptor has anti-allodynic effects in this condition, suggesting that the melanocortin system plays a role in neuropathic pain. A natural agonist of melanocortin receptors is alpha-melanocyte-stimulating hormone (alpha-MSH), derived from the precursor molecule pro-opiomelanocortin (POMC). Cleavage of this precursor also yields beta-endorphin, which is co-released with alpha-MSH in nociception-associated areas of the spinal cord. We hypothesise that melanocortin receptor blockade attenuates a tonic influence of alpha-MSH on nociception, thus allowing the analgesic effects of beta-endorphin to develop, resulting in the alleviation of allodynia. In this way, treatment with melanocortin receptor antagonists might enhance opioid efficacy in neuropathic pain, which would be of great benefit in clinical practice.
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PMID:Neuropathic pain: a possible role for the melanocortin system? 1169 27

Agouti signaling protein (ASIP), the human (h) homolog of agouti, is an endogenous melanocortin peptide antagonist. To date, characterization of this protein has been performed with recombinant protein only and without the availability of an ASIP/agouti radioligand. In this report we describe the functional characteristics of a chemically synthesized truncated ASIP variant, ASIP-[90-132 (L89Y)], and the binding characteristics of its cognate radioligand, (125)I-ASIP-[90-132 (L89Y)]. Similar to full-length recombinant ASIP/agouti, ASIP-[90-132 (L89Y)] was a potent inhibitor of alpha-melanocyte-stimulating hormone cAMP generation at the cloned human melanocortin receptor (hMCR) subtypes hMC1R and hMC4R. It also displayed a lesser degree of inhibition at the hMC3R and hMC5R. However, ASIP-[90-132 (L89Y)] was found to be less potent than full-length recombinant ASIP and, surprisingly, only exhibited weak inhibitory activity at the hMC2R. In competition binding assays with the radioligand (125)I-ASIP-[90-132 (L89Y)], ASIP-[90-132 (L89Y)] displayed a hierarchy of binding affinity that roughly paralleled its rank order of inhibitory potency at the various MCR subtypes, i.e., hMC1R approximately hMC4R > hMC3R approximately hMC5R > hMC2R. Structure-activity studies revealed that ASIP-[90-132 (L89Y)] possessed greater pharmacological potency than either the further truncated ASIP variants ASIP-(116-132) or cyclo(CRFFRSAC). Interestingly, the latter molecules were both weak agonists at the hMC1R. These studies further support the concept that ASIP/agouti inhibits melanocortin action by directly binding to target MCRs and provide additional insight into the structural requirements for maximal inhibitory potency.
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PMID:Functional properties of an agouti signaling protein variant and characteristics of its cognate radioligand. 1170 73

Many lines of evidence indicate that the activity of sebaceous glands can be modulated by neuropeptides. Direct evidence in man, however, is still missing. We show that SZ95 sebocytes, an immortalized human sebaceous gland cell line, express receptors for alpha-melanocyte-stimulating hormone. Reverse transcription polymerase chain reaction with primers against the five melanocortin receptors and immunofluorescence studies using an antibody directed against a peptide corresponding to the amino acids 2-18 of the human melanocortin-1 receptor disclosed specific transcripts and immunoreactivity for melanocortin-1 receptor in these cells. Melanocortin-1 receptor expression was confirmed in sebocytes of normal human skin by immunohistochemistry. In contrast, no immunostaining for the melanocortin-5 receptor could be detected in sebocytes in situ, in accordance with the lack of specific transcripts for this melanocortin receptor in SZ95 sebocytes. As cytokines play an important role in the recruitment of inflammatory cells in acne and related disorders and alpha-melanocyte-stimulating hormone exerts immunomodulatory effects in many other cell types, we investigated the effect of alpha-melanocyte-stimulating hormone on interleukin-8 secretion by SZ95 sebocytes. Treatment with interleukin-1beta resulted in a marked increase in interleukin-8 release that was partially blocked by coincubation with alpha-melanocyte-stimulating hormone in a dose-dependent manner. Taken together, we show here that the melanocortin-1 receptor is expressed in vitro and in situ in human sebocytes. By modulating interleukin-8 secretion, alpha-melanocyte-stimulating hormone may act as a modulator of inflammatory responses in the pilosebaceous unit.
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PMID:Evidence for expression of melanocortin-1 receptor in human sebocytes in vitro and in situ. 1187 95

Bioactive peptides derived from the prohormone, pro-opiomelanocortin (POMC), are generated in neurons of the hypothalamus and act as endogenous ligands for the melanocortin-4 receptor (MC4R), a key molecule underlying appetite control and energy homeostasis. It is therefore important to understand many aspects of POMC gene regulation in the brain, as pharmacological manipulation of POMC expression/processing could be a potential strategy to combat obesity. Most studies that have analysed POMC gene expression in the hypothalamus have focused on gene transcription experiments. Ultimately, however, factors that regulate post-translational processing and secretion of peptides will have most bearing on melanocortin signalling. This article focuses on (a) current evidence that POMC is involved in obesity, (b) how POMC transcription is regulated in the hypothalamus, (c) the mechanism by which proteolytic processing of POMC is controlled in the hypothalamus and what peptides are produced and (d) which POMC-derived peptides are the most potent ligands at the melanocortin receptor in vitro and in vivo. It seems that post-translational cleavage of POMC in the hypothalamus may be regulated with respect to energy requirement. We predict that further research into hypothalamic POMC processing, and the proteolytic enzymes involved, may yield important new clues on how flux through the MC4R pathway is regulated.
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PMID:Pro-opiomelanocortin processing in the hypothalamus: impact on melanocortin signalling and obesity. 1187 90


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