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)

Proopiomelanocortin (POMC) is a precursor of ACTH, beta- and gamma-liportopins, alpha-, beta- and gamma-MSH, beta-endorphin. alpha-, beta- and gamma-MSH are synthesized by hypothalamus neurons, and leptin stimulates their synthesis. These hormones regulate food consumption and energy metabolism by via melanocortin receptors (MC3-R and MC4-R) in hypothalamus. Screening mutations in the coding region of human POMC has been carried out with PCR, SSCP and DNA sequencing and the association study of these mutations and human obesity has been performed. Group of patients with the exogenous obesity (BMI 37.8 +/- 6.8 kg/m2) consisted of 228 persons (173 women and 55 men). 145 blood donors (67 women and 78 men) without obesity (BMI J25 kg/m2, 23.1 +/- 2.2 kg/m2) and 170 women without apparent obesity at the beginning of the study were included in the control group. 8 polymorph sites: insertions; missense and silent mutations have been identified in the coding region of POMC. Among them 1) two heterozygous mutations: the insertion of 6 b.p. (GGGCCC) in codon 176 inducing the insertion of two amino acid residues (Arg-Ala) in POMC and nonsense mutation (G-7316-T) in codon 180 of gamma-LTH coding region of the same DNA chain were identified in 4 women (5.8%) out of 69 patients with morbid obesity (BMI 40-53 kg/m2). These mutations were not found in control (n = 315). 2) The new heterozygous mutation T-7130-C (Phe118Leu) in active site of alpha-MSH has been identified in POMC gene of a woman suffering with obesity since the early childhood. 3) Mutation A-7341-G (Glu188Gly) seemed to have a protective effect because it was revealed more frequently in control (3.9%) than in obese patients (0.66%). The results of genetic study of two pedigrees suggested the dominant influence of the first two mutations (1 and 2) on woman obesity.
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PMID:[Screening of mutations in genes of pro-opiomelanocortin in patients with constitutional exogenous obesity]. 1206 94

The molecular basis of ligand recognition by the melanocortin 4 receptor (MC4R) has not been fully defined. In this study, we investigated the molecular determinants of MC4R ligand binding, employing a large array of ligands, using three approaches. First, molecular modeling of the receptor was used to identify Phe284, in transmembrane (TM) 7, as a potential site of ligand interaction. Mutation of Phe284 to alanine reduced binding affinity and potency of peptides containing L-Phe by up to 71-fold but did not appreciably affect binding of linear peptides containing D-Phe, consistent with a hydrophobic interaction between the Phe7 of alpha-melanocyte-stimulating hormone and Phe284. Second, we examined the effect of a naturally occurring mutation in TM3 (I137T) that is linked to obesity. This mutation decreased affinity and potency of cyclic, rigid peptides but not more flexible peptides, consistent with an indirect effect of the mutation on the tertiary structure of the receptor. Third, we examined the residues that support ligand selectivity for the MC4R over the MC3R. Mutation of Ile125 (TM3) of the MC4R to the equivalent residue of the MC3R (phenylalanine) selectively decreased affinity and potency of MC4R-selective ligands. This effect was mirrored by the reciprocal MC3R mutation F157I. The magnitude of this effect indicates that this locus is not of major importance. However, it is considered that an isoleucine/phenylalanine mutation may affect the orientation of Asp122, which has been identified as a major determinant of ligand binding affinity. Thus, this study provides further characterization of the MC4R binding pocket.
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PMID:Molecular determinants of melanocortin 4 receptor ligand binding and MC4/MC3 receptor selectivity. 1260 99

Leptin, the obese gene product, was reported to stimulate prolactin (PRL) secretion, but the neuroendocrine mechanism underlying this hormonal response is largely unknown. Thus, in this study we examined the involvement of several important PRL regulators in the leptin-induced PRL secretion in male rats. Compared with the values in normally fed rats, food deprivation for 3 days significantly decreased both PRL and leptin levels in the plasma. These changes were reverted to normal by a 3-day constant infusion of 75 microg/kg/day of leptin to the fasted rats, while 225 microg/kg/day of leptin further elevated both PRL and leptin levels. These four groups of animals were used for the following experiments. Results of dopamine and serotonin turnover studies in the brain and the pituitary indicated that neither of these biogenic amines plays a primary role in mediating leptin's effects on PRL. Repeated intracerebroventricular injections over 72 h of neutralizing antibodies against vasoactive intestinal peptide, PRL-releasing peptide, or beta-endorphin, did not significantly suppress the leptin actions. However, both the blockade of the melanocortin (MC) 4 receptor (R) and the immunoquenching of brain alpha-melanocyte-stimulating hormone (alpha-MSH) completely abolished the leptin-induced PRL release, and the stimulation of the MC4-R, but not the MC3-R, significantly elevated PRL levels in the fasted rats. These results suggest that alpha-MSH, a cleaved peptide from pro-opiomelanocortin of which synthesis is stimulated by leptin, may be the pivotal neuropeptide in the brain mediating the leptin's stimulatory influence on PRL secretion. It was also suggested that the MC4-R may be the primary subtype of the MC-Rs mediating this action of alpha-MSH.
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PMID:Pivotal roles of alpha-melanocyte-stimulating hormone and the melanocortin 4 receptor in leptin stimulation of prolactin secretion in rats. 1267 10

Melanocortin receptors (MC-R) activated by one of several peptides derived from the pro-opiomelanocortin (POMC) precursor have become leading contenders for a pivotal role in controlling food intake. Evidence has emerged over the last decade to implicate primarily the MC4-R and, to a lesser extent, MC3-R as the key sub-types involved and both are strategically located in those regions within the hypothalamus known to be associated with feeding. The receptors are within class A of the GPCR superfamily and the key electrostatic interaction with the positively charged peptide (Arg) has been mapped to one or more Asp or Glu residues located on helices II and III of the seven helical bundle characteristic of this class of receptor. Sites for secondary interactions from which sub-type selectivity may be derived have also been located in the extracellular and helical domains. Unique amongst GPCRs is the presence of endogenous antagonist peptides, Agouti and Agouti-related peptide (AGRP), which confer an extra level of control on the system. Recently, several reports of potent and selective non-peptide ligands have been published and these are seen as prototypic molecules from which drugs may emerge to treat obesity (agonists) and cachexia (antagonists). The role played by the melanocortin system is the subject of this review and advances in our understanding of the structure of the endogenous ligand(s), non-peptide, small molecule ligands and the receptors at which they interact will be discussed.
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PMID:The melanocortin system and its role in obesity and cachexia. 1267 37

We have developed an in vitro assay for pre-pro-neuropeptide synthesis and processing. Mouse proopiomelanocortin (POMC) cDNA was cloned into a vector containing T7 promoter. In vitro transcription and translation were carried out to produce the proopiomelanocortin peptide. The pro-peptide was processed by incubating with cell extract of mouse and rat pituitary cell lines. The activity of processed mature peptide was tested in a cell line expressing human melanocortin 4 receptor (MC4R). Using this approach, we produced biologically active alpha-melanocyte-stimulating hormone (alpha-MSH). Furthermore, we developed a universal functional assay for G-protein-coupled receptors (GPCRs) using a reporter gene assay. More than 20 different GPCRs were examined using this functional assay. Our results demonstrated that the activity of all GPCRs could be measured by the functional assay. It should be possible to identify novel bioactive peptides for orphan GPCRs by the combination of in vitro processing and GPCR functional assays.
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PMID:Generation of a bioactive neuropeptide in a cell-free system. 1269 24

Heterozygous coding mutations in the melanocortin 4 receptor (MC4R) are implicated in 1 to 6% of early onset or severe adult obesity cases. To better address the problem of the genotype:phenotype relationship within this specific form of obesity, we systematically studied the functional characteristics of 50 different obesity-associated MC4R mutations. Structure modeling of MC4R indicates that obesity-associated MC4R mutations are not localized in a single domain of the protein. We developed a flow cytometry-based assay to compare cell membrane expression of obesity-associated MC4R mutants. Using this assay, we demonstrate that over 54% of the obesity-associated MC4R mutations impair the membrane expression of MC4R. All other mutations impair the basal constitutive activity and/or the EC(50) for the physiological agonist alpha-MSH as measured in a cAMP- dependent luciferase assay. The extent of the alterations in receptor activity ranges from a total suppression of MC4R activation in response to alpha-MSH to a mild alteration of the basal constitutive activity of the receptor. Since most patients are heterozygous for MC4R mutations, these data indicate that a small decrease in overall MC4R activity can cause obesity, strongly supporting the hypothesis that the MC4R is a critical component of the adipostat in humans.
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PMID:Molecular genetics of human obesity-associated MC4R mutations. 1285 Dec 97

The intermediate lobe of rodent pituitaries is involved in the regulation of prolactin (PRL) secretion from the anterior lobe. In a previous study, we demonstrated the stimulatory effect of alpha-melanocyte-stimulating hormone (alpha-MSH) on PRL release and the expression of melanocortin-3 receptors (MC3-Rs) in cultured mouse pituitary cells. The aim of the present study was to clarify whether alpha-MSH directly stimulates PRL release through the MC3-Rs by determining the cell type of MC3-R-expressing cells in the mouse pituitary anterior lobe. Northern blot analysis revealed a 2.7-kb transcript for MC3-R mRNA in the anterior and neurointermediate lobes of pituitary glands of adult male and female mice. Dual cellular localization of MC3-R mRNA and PRL or growth hormone (GH) in the mouse pituitary glands was performed by in situ hybridization analysis of MC3-R mRNA followed by immunocytochemical detection of PRL or GH. MC3-R mRNA was detected in most mammotropes and some somatotropes. alpha-MSH increased PRL release and stimulated DNA replication in mammotropes, and these effects were blocked by SHU9119, an antagonist of MC3-R and MC4-R. These results indicate that alpha-MSH stimulates PRL release and proliferation of mammotropes through MC3-Rs, and suggest that alpha-MSH from intermediate lobes can regulate mammotrope functions in the mouse pituitary.
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PMID:Alpha-melanocyte-stimulating hormone stimulates prolactin secretion through melanocortin-3 receptors expressed in mammotropes in the mouse pituitary. 1291 62

Activation of central melanocortin receptors (MCR) inhibits fever but can also stimulate thermogenesis, and the mechanisms involved are unknown. To determine whether the long-recognized antipyretic effect of exogenous alpha-MSH is mediated by the melanocortin-4 receptor (MC4R), and what thermoeffector systems are involved, we tested the effects of intracerebroventricular (i.c.v.) injection of alpha-MSH on lipopolysaccharide (LPS, 30 microg/kg i.p.)-induced fever in rats, in the presence and absence of the selective MC4R antagonist HS014. Treatment with alpha-MSH (1 microg, i.c.v.) suppressed LPS-induced increases in core body temperature (Tc), whereas a lower dose (300 ng) was ineffective. Nevertheless, both alpha-MSH doses effectively inhibited LPS-induced peripheral vasoconstriction, the principal heat-conserving thermoeffector, as determined by changes in tail skin temperature (Tsk). This implies that the net antipyretic effect of alpha-MSH cannot be accounted for solely by modulation of heat loss effectors, but also involves other mechanisms. Surprisingly, central MC4-R blockade by coinjected HS014 (1 microg) not only prevented, but reversed the effect of alpha-MSH (1 microg) on Tc, thus resulting in augmented LPS-induced fever. In afebrile rats, alpha-MSH infusion caused a modest transient increase in Tc that was blocked by coinjected HS014, but was not accompanied by altered Tsk. Overall, the results support the hypothesis that the MC4R mediates the antipyretic effects of alpha-MSH. Paradoxically, in the presence of pharmacological MC4-R blockade during fever, exogenous alpha-MSH can exacerbate fever, probably by acting via other central MCR subtype(s). In normal animals, centrally injected alpha-MSH exerts a hyperthermic effect that is mediated by the MC4R, consistent with recent evidence that MC4R activation promotes energy expenditure in normal states through stimulation of thermogenesis.
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PMID:Roles of the melanocortin-4 receptor in antipyretic and hyperthermic actions of centrally administered alpha-MSH. 1497 64

To clarify the neuronal mechanism of the hypothalamic melanocortin system in regulating energy metabolism, we investigated the effects of centrally administered alpha-melanocyte-stimulating hormone (alpha-MSH) and agouti-related protein (AGRP), an agonist and an antagonist for the melanocortin 4 receptor (MC4-R), respectively, on the activity of sympathetic nerves innervating brown adipose tissue (BAT) and on BAT temperature. A bolus infusion of alpha-MSH (1 nmol) into the third cerebral ventricle (i3vt) significantly increased sympathetic nerve activity and elevated BAT temperature (P<0.05). The i3vt infusion of AGRP (1 nmol) gradually suppressed BAT sympathetic nerve activity and was accompanied by a significant reduction in BAT temperature (P<0.05). In conclusion, the hypothalamic melanocortin system may regulate peripheral energy expenditure, as well as thermogenesis, through its influence on BAT sympathetic nerve activity.
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PMID:Hypothalamic melanocortin system regulates sympathetic nerve activity in brown adipose tissue. 1498 15

The melanocortin 4 receptor (MC4-R) is a Galpha s-coupled receptor known to increase cAMP production following agonist stimulation. We demonstrate that the mitogen-activated protein kinases p42 (ERK2) and p44 (ERK1) are also activated by MC4-R following treatment with the MC4-R agonist NDP-alpha-MSH in stably transfected CHO-K1 cells. This time- and dose-dependent response is abolished by the MC4-R antagonist SHU-9119. p42/p44 MAPK activation is blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 but not by the protein kinase A (PKA) inhibitor Rp-cAMPS, indicating that that signal activating the p42/p44 MAPK pathway is conveyed through inositol triphosphate.
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PMID:Activation of MAP kinase by MC4-R through PI3 kinase. 1517 28


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