UNIPROT:P01189 - FACTA Search

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)

A number of studies suggest the involvement of melanocortins in nociception, and although the mechanism through which this occurs is still unknown, experimental evidence would suggest an involvement of melanocortin MC(4) receptors. We investigated the effect of melanocortin receptor agonist and antagonists on nociceptive behaviour induced by formalin in the mouse. The intrathecal injection of the melanocortin receptor agonist MTII ([Ac-Nle(4),Asp(5),D-Phe(7),Lys(10)]cyclo-alpha-MSH-(4-10) amide) (5 nmol; P<0.05) significantly increased nociception in both phases of the formalin test, whereas the synthetic melanocortin receptor antagonists, SHU9119 ([Ac-Nle(4),Asp(5),D-2-Nal(7),Lys(10)]cyclo-alpha-MSH-(4-10) amide) (5 nmol), HS014 ([Ac-Cys(11),D-2-Nal(14),Cys(18)]beta-MSH-(11-22)amide) (5 nmol), and JKC-363 (cyclic [Mpr(11),D-Nal(14),Cys(18),Asp(22)-NH(2)]beta-MSH-11-22)) (5 nmol), and the endogenous receptor antagonist Agouti-related protein (AgRP) (1.5 nmol) were effective in reducing nociception in the late phase of the formalin test (50-60% of reduction in licking/flinching response; P<0.05). The present findings further support the involvement of the melanocortin system in the control of nociception. Moreover, considering that melanocortin MC(4) receptors are the only melanocortin subtype receptors present in the spinal cord, we can assume that the activity of the peptides in the formalin model is mediated through melanocortin MC(4) receptors.
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PMID:Melanocortin receptor agonists and antagonists modulate nociceptive sensitivity in the mouse formalin test. 1466 13

The melanocortin-4 (MC4) receptor may possibly be involved in stress and stress-related behavior. In the present study, we examined effects of an intracerebroventricular injection of the MC4 receptor agonist, Ac-[Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH 4-10-NH2 (MT II), and the MC4 receptor inverse agonist, Agouti-related protein (AGRP), on dorsal raphe nucleus (DRN) serotonergic neurons and the locus coeruleus (LC) noradrenergic neurons, both of which are brain neuronal systems related to responses to stress. The firing rate of DRN serotonergic neurons was increased by MTII, while AGRP had a lack of effect on the firing rate of DRN serotonergic neurons. In comparison with the DRN, MTII significantly reduced the firing rate of LC noradrenergic neurons, while AGRP increased LC neuronal activity. These findings suggest that MC4 receptor ligands differently regulate serotonergic and noradrenergic neuronal systems. The MC4 receptor mediating multiple regulation on the monoaminergic neuronal system may, in part, relate to stress responses (anxiety and/or depressive behavior).
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PMID:Electrophysiological effects of melanocortin receptor ligands on neuronal activities of monoaminergic neurons in rats. 1466 15

The G-protein-coupled melanocortin receptors (MCRs) play an important role in a variety of essential functions such as the regulation of pigmentation, energy homeostasis, and steroid production. We performed a comprehensive characterization of the MC system in Fugu (Takifugu rubripes). We show that Fugu has an AGRP gene with high degree of conservation in the C-terminal region in addition to a POMC gene lacking gamma-MSH. The Fugu genome contains single copies of four MCRs, whereas the MC3R is missing. The MC2R and MC5R are found in tandem and remarkably contain one and two introns, respectively. We suggest that these introns were inserted through a reverse splicing mechanism into the DRY motif that is widely conserved through GPCRs. We were able to assemble large blocks around the MCRs in Fugu, showing remarkable synteny with human chromosomes 16 and 18. Detailed pharmacological characterization showed that ACTH had surprisingly high affinity for the Fugu MC1R and MC4R, whereas alpha-MSH had lower affinity. We also showed that the MC2R gene in Fugu codes for an ACTH receptor, which did not respond to alpha-MSH. All the Fugu receptors were able to couple functionally to cAMP production in line with the mammalian orthologs. The anatomical characterization shows that the MC2R is expressed in the brain in addition to the head-kidney, whereas the MC4R and MC5R are found in both brain regions and peripheral tissues. This is the first comprehensive genomic and functional characterization of a GPCR family within the Fugu genome. The study shows that some parts of the MC system are highly conserved through vertebrate evolution, such as regions in POMC coding for ACTH, alpha-MSH, and beta-MSH, the C-terminal region of AGRP, key binding units within the MC1R, MC2R, MC4R, and MC5R, synteny blocks around the MCRs, pharmacological properties of the MC2R, whereas other parts in the system are either missing, such as the MC3R and gamma-MSH, or different as compared to mammals, such as the affinity of ACTH and MSH peptides to MC1R and MC4R and the anatomical expression pattern of the MCRs.
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PMID:The melanocortin system in Fugu: determination of POMC/AGRP/MCR gene repertoire and synteny, as well as pharmacology and anatomical distribution of the MCRs. 1469 81

Interactions between pro-opiomelanocortin (POMC)-derived peptides, agouti-related protein (AGRP) and the melanocortin-4 receptor (MC4-R) are central to energy homeostasis. In this study we have undertaken comprehensive pharmacological analysis of these interactions using a CHOK1 cell line stably transfected with human MC4-R. Our main objectives were (1) to compare the relative affinities and potencies of POMC-derived peptides endogenously secreted within the hypothalamus, (2) to investigate the potency of AGRP(83-132) antagonism with respect to each POMC-derived peptide and (3) to determine whether AGRP(83-132) and POMC-derived peptides act allosterically or orthosterically. We have found that beta melanocyte-stimulating hormone (betaMSH), desacetyl alpha MSH (da-alphaMSH) and adrenocorticotrophic hormone all have very similar affinities and potencies at the MC4-R compared with the presumed natural ligand, alphaMSH. Moreover, even MSH precursors, such as beta lipotrophic hormone, showed significant binding and functional activity. Therefore, many POMC-derived peptides could have important roles in appetite regulation and it seems unlikely that alphaMSH is the sole physiological ligand. We have shown that AGRP(83-132) acts as a competitive antagonist. There was no significant difference in the potency of inhibition by AGRP(83-132) or agouti(87-132) at the MC4-R, regardless of which POMC peptide was used as an agonist. Furthermore, we have found that AGRP(83-132) has no effect on the dissociation kinetics of radiolabelled Nle4,D-Phe7 MSH from the MC4-R, indicating an absence of allosteric effects. This provides strong pharmacological evidence that AGRP(83-132) acts orthosterically at the MC4-R to inhibit Gs-coupled accumulation of intracellular cAMP.
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PMID:Agouti-related protein (83-132) is a competitive antagonist at the human melanocortin-4 receptor: no evidence for differential interactions with pro-opiomelanocortin-derived ligands. 1470 57

The importance of the central melanocortin system in the regulation of energy balance is highlighted by studies in transgenic animals and humans with defects in this system. Mice that are engineered to be deficient for the melanocortin-4 receptor (MC4R) or pro-opiomelanocortin (POMC) and those that overexpress agouti or agouti-related protein (AgRP) all have a characteristic obese phenotype typified by hyperphagia, increased linear growth, and metabolic defects. Similar attributes are seen in humans with haploinsufficiency of the MC4R. The central melanocortin system modulates energy homeostasis through the actions of the agonist, alpha-melanocyte-stimulating hormone (alpha-MSH), a POMC cleavage product, and the endogenous antagonist AgRP on the MC3R and MC4R. POMC is expressed at only two locations in the brain: the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the tractus solitarius (NTS) of the brainstem. This chapter will discuss these two populations of POMC neurons and their contribution to energy homeostasis. We will examine the involvement of the central melanocortin system in the incorporation of information from the adipostatic hormone leptin and acute hunger and satiety factors such as peptide YY (PYY(3-36)) and ghrelin via a neuronal network involving POMC/cocaine and amphetamine-related transcript (CART) and neuropeptide Y (NPY)/AgRP neurons. We will discuss evidence for the existence of a similar network of neurons in the NTS and propose a model by which this information from the ARC and NTS centers may be integrated directly or via adipostatic centers such as the paraventricular nucleus of the hypothalamus (PVH).
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PMID:The central melanocortin system and the integration of short- and long-term regulators of energy homeostasis. 1474 11

Two Finnish cohorts, comprising 56 children with severe early-onset obesity (relative weight for height greater than or equal to +70% before age 10) and 252 morbidly obese adults (body mass index, > or = 40 kg/m(2)), were screened for melanocortin-4 receptor (MC4R) mutations. We identified a pathogenic mutation (S127L) in one child, causing severe early-onset obesity. We describe the phenotype of this particular mutation for the first time. We also identified a novel (I226T) polymorphism in the coding and two new variations (-439delGC and 1059C>T) outside the coding region of the MC4R gene. Three previously described polymorphisms (V103I, T112M, and I125L) were identified. In vitro functional studies of variants T112M, S127L, and I226T supported a pathogenic role of the S127L mutation, because signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma(1)-MSH were impaired. The S127L mutation did not affect receptor inhibition by the antagonist agouti-related protein. Localization of the three variant receptors was similar to that of wild type. In conclusion, a pathogenic MC4R mutation was found among subjects with severe early-onset obesity but not among morbidly obese adults. Impaired function of the S127L receptor was due to reduced activation, not a defect of protein transport to the cell membrane.
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PMID:Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese finnish children and adults. 1476 18

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

In several hyperphagic models, including lactation, in which hypothalamic melanocortin signaling is reduced, a novel expression of NPY mRNA in the dorsomedial hypothalamus (DMH) has been observed, suggesting that melanocortin signaling and the induced NPY in the DMH may constitute unique neurocircuitry in mediating energy balance. Using lactating rats as a model, the present study first showed that in the DMH abundant alpha-MSH and agouti-related protein fibers are in close apposition to NPY-positive cells. However, no NPY and MC4R (a melanocortin receptor) double-labeled neurons were observed. These data suggested that melanocortin input may synapse on presynaptic terminals that then synapse on DMH NPY cells. To study the function of DMH MC4Rs in energy balance, an MC3/4R-selective agonist, melanotan II (MTII), was injected bilaterally into the DMH. MTII injection significantly suppressed feeding induced by 24 hr fasting or suckling-induced hyperphagia. Furthermore, MTII treatment greatly attenuated suckling-induced NPY expression in the DMH. MTII treatment also stimulated uncoupling protein 1 activity in the brown adipose tissue of suckling female rats, indicative of increased sympathetic outflow. In summary, the present study demonstrated that the melanocortin system in the DMH not only plays an important role in inducing NPY expression in the DMH of lactating rats but also in regulating energy homeostasis, at least in part, by modulating appetite and energy expenditure.
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PMID:Melanocortin 4 receptor-mediated hyperphagia and activation of neuropeptide Y expression in the dorsomedial hypothalamus during lactation. 1517 78

Animals have developed highly adaptive and redundant mechanisms to maintain energy balance by matching caloric intake to caloric expenditure. Recent evidence has pointed to a variety of peripheral signals that inform specific central nervous system (CNS) circuits about the status of peripheral energy stores as critical to the maintenance of energy balance. A critical component of these CNS circuits is the melanocortin system. Regulation of signaling by melanocortin 3 and melanocortin 4 receptors in the CNS is controlled via neuronal cell bodies in the arcuate nucleus of the hypothalamus that synthesize melanocortin receptor agonists such as alpha-melanocyte-stimulating hormone (alpha-MSH) or antagonists such as agouti-related protein (AgRP). The activity of these two populations of neurons is reciprocally regulated by a number of peripheral and central systems that influence energy balance. Further, increased melanocortin signaling via pharmacological or genetic means in the CNS causes potent reductions in food intake and weight loss. Decreased melanocortin signaling via pharmacological or genetic means results in increased food intake and weight gain. Reviewed here is the wide range of evidence that points to the melanocortin system as a critical node in the diverse neurocircuitry that regulates food intake and body weight.
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PMID:The critical role of the melanocortin system in the control of energy balance. 1518 16

Treatment for 40 h of reaggregate pituitary cell cultures from 14-day-old female rats with nanomolar concentrations of gamma3-melanocyte-stimulating hormone (MSH) increased prolactin mRNA but not growth hormone (GH) mRNA expression levels as measured by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). During the 40 h incubation, gamma3-MSH stimulated prolactin accumulation in the culture medium. alpha-MSH, a potent agonist of the rat melanocortin-3 receptor (MC3R) and Ala(8)-gamma2-MSH, a very weak agonist of the MC3R, increased prolactin mRNA expression at a similar concentration range as gamma3-MSH. The effect of gamma3-MSH on prolactin mRNA expression was abolished when aggregates were cultured in the presence of thyroid or glucocorticoid hormones, but not of oestradiol. By contrast, oestradiol abolished the stimulatory effect of Ala(8)-gamma2-MSH on prolactin mRNA expression. In GH3 cells stably transfected with the enhanced green fluorescent protein (eGFP) gene under control of a 3-kb prolactin promoter fragment, a dose as low as 1 nMgamma3-MSH, added for 24 h, significantly increased eGFP fluorescence. Agouti-related protein (AgRP(83-132)), a known endogenous MC3R and MC4R antagonist, did not reduce the stimulation of prolactin mRNA expression by gamma3-MSH or Ala(8)-gamma2-MSH. On its own, AgRP(83-132) significantly increased prolactin mRNA expression level and prolactin accumulation. Both gamma2-MSH and Ala(8)-gamma2-MSH increased [S(35)]GTPgammaS binding in membrane preparations of 14-day-old rat pituitaries and of GH3 cells. Whereas MC3R and MC5R mRNA were detectable by RT-PCR in normal pituitary, these receptor mRNAs were undetectable in GH3 cells using various oligonucleotide primer sets. The present findings indicate that melanocortin peptides stimulate prolactin gene expression and production and that, at least in part, a receptor different from the classic MCR is involved. AgRP appears to have other actions than its known antagonistic activity on the MC3R and MC4R.
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PMID:Melanocortin peptides stimulate prolactin gene expression and prolactin accumulation in rat pituitary aggregate cell cultures. 1527 Oct 62

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