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)

POMC (31,000 MW) is localized to the pituitary, brain, skin, and other peripheral sites. The particular enzyme profile present within a cell dictates the nature of the hormonal ligand (melanocortin) synthesized and secreted: melanotropic peptides (alpha-MSH beta-lipotropin, lambda-MSH), corticotropin (ACTH), several endorphins (e.g., met-enkephalin). These POMC-derived peptides mediate their actions through typical seven-spanning membrane receptors (MCRs; MCR1, 2, 3, 4, and 5). A specific melanocortin acting on a specific MCR regulates a particular biological response; for example, alpha-MSH on MCR1 increases melanogenesis within melanocytes, ACTH on MCR2 increases cortisol production within adrenal zona fasciculata cells. Within the brain melanocortins regulate satiety (MCR4) and erectile activity (MCR?). MCRs have been localized by melanocortin macromolecular probes, for example, fluorescent to human epidermal melanocytes and also to keratinocytes, suggesting that systemic melanocortins or localized POMC products might regulate these integumental cellular elements in synchrony to enhance skin pigmentation and/or immunological responses. Superpotent, prolonged acting melanotropic peptides have been synthesized and their application in clinical medicine has been demonstrated. MCR antagonists have been used to discover and further delineate other roles of melanocortin ligands. For example, melanocortin-induced satiety can be antagonized by a melanocortin antagonist. Defects in melanocortin ligand biosynthesis, secretion, and melanocortin receptor function can lead to a diverse number of pathological states.
 ...
PMID:The proopiomelanocortin system. 1081 38

Agouti protein and Agouti-related protein (Agrp) are paracrine signaling molecules that act by antagonizing the effects of melanocortins, and several alternatives have been proposed to explain their mechanisms of action. Genetic crosses in a sensitized background uncover a phenotypic difference between overexpression of Agouti and loss of Mc1r function, demonstrate that a functional Mc1r is required for the pigmentary effects of Agouti, and suggest that Agouti protein can act as an agonist of the Mc1r in a way that differs from alpha-MSH stimulation. In vitro, Agouti protein inhibits melanocortin action by two mechanisms: competitive antagonism that depends on the carboxyterminus of the protein, and downregulation of melanocortin receptor signaling that depends on the aminoterminus. Our findings provide evidence of a novel signaling mechanism whereby alpha-MSH and Agouti protein function as independent ligands that inhibit each other's binding and transduce opposite signals through a single receptor.
 ...
PMID:Molecular pharmacology of Agouti protein in vitro and in vivo. 1081 47

The neuropeptide, alpha-melanocyte-stimulating hormone (alpha-MSH) is well known for its immunomodulating capabilities. alpha-MSH antagonizes the activity of numerous proinflammatory mediators; for example, Interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha (TNF alpha), and bacterial endotoxin. In vivo alpha-MSH has been shown to suppress a contact hypersensitivity reaction in mice, and to induce hapten-specific tolerance. Since antigen presenting cells (APC) represent key elements for tolerance induction, the effect of alpha-MSH, and the expression of its receptor-melanocortin receptor-1 (MC-1R), on human peripheral blood-derived monocytes and dendritic cells (DC), was investigated. Semiquantitative RT-PCR demonstrated that monocytes and DC express MC-1R, but none of the other members of the MC-receptor family. Moreover, the extent of MC-1R expression correlated with the state of activation of these cells. Since the major ligand of MC-1R is alpha-MSH the question of whether alpha-MSH affects the function of monocyte derived DC was further investigated. We found that the expression of the costimulatory molecules CD 86 and CD 40 was downregulated on DC in the presence of alpha-MSH. Thus, alpha-MSH may exert its immunosuppressive effects by altering the function of APC.
 ...
PMID:Human peripheral blood-derived dendritic cells express functional melanocortin receptor MC-1R. 1081 52

Human dermal microvascular endothelial cells (HDMEC) are capable of mediating leukocyte-endothelial interactions by the expression of cellular adhesion molecules and the release of proinflammatory cytokines and chemokines during cutaneous inflammation. Recent studies support the important role for proopiomelanocortin (POMC) peptides, such as alpha-melanocyte stimulating hormone (alpha-MSH), as immunomodulators in the cutaneous immune system. The purpose of the studies described here was to determine whether HDMEC serves as both target and source for POMC peptides. RT-PCR and Northern blot studies demonstrated the constitutive expression of mRNA for the adrenocorticotropin (ACTH) and alpha-MSH-specific melanocortin receptor 1 (MC-1R) in HDMEC, and the microvascular endothelial cell line HMEC-1 that could be upregulated by stimulation with IL-1 beta and alpha-MSH. HDMEC responded to stimulation by alpha-MSH with a dose- and time-dependent synthesis and release of the CXC chemokines, IL-8 and GRO alpha. Likewise, alpha-MSH augmented HDMEC chemokine release induced by TNF or IL-1. HD-MEC were found to constitutively express POMC and prohormone convertase 1 (PC-1); the latter being required to generate ACTH from the POMC prohormone. POMC and PC-1 mRNA expression are increased as a result of stimulation with UVB and UVA1 radiation, IL-1, and alpha-MSH. In addition, UV-radiation is capable of inducing the release of HDMEC, ACTH, and alpha-MSH in a time- and dose-dependent fashion. Thus, these data provide evidence that HDMEC are capable of expressing functional MC-1R, POMC, and PC-1 mRNA; and of releasing POMC peptides with UV light, IL-1, and alpha-MSH as regulatory factors. The expression and regulation of these peptides may be of importance, not only for the autocrine or paracrine regulation of physiologic functions of dermal endothelial cells, but also for the regulation of certain microvascular-mediated cutaneous or systemic inflammatory responses.
 ...
PMID:Expression of functional melanocortin receptors and proopiomelanocortin peptides by human dermal microvascular endothelial cells. 1081 57

The melanocortins alpha- and gamma-melanocyte-stimulating hormones (alpha- and gamma-MSH) derive from the pro-opiomelanocortin (POMC) precursor. Melanocortins exert a wide range of biological activities in the brain through activation of at least three distinct melanocortin receptor (MC-R) subtypes. In order to determine whether POMC neurones can modulate their own activity, we looked for the possible expression of the MC3-R gene in POMC-positive cell bodies in the rat hypothalamus. In situ hybridization experiments revealed that the density of MC3-R mRNA is particularly high in the arcuate nucleus which contains the main population of POMC neurones in the brain. The occurrence of MC3-R mRNA in POMC-positive cell bodies was demonstrated using a double-labelling in situ hybridization technique. The proportion of POMC neurones expressing MC3-R mRNA was significantly higher in the most rostral (43.5%) than in the most posterior part of the arcuate nucleus (8.2%). These results indicate that melanocortins likely exert a direct regulatory feedback on POMC neurones through activation of MC3-R receptors. Our data also suggest that MC3-R may be involved in the neuroendocrine responses induced by centrally administered melanocortins.
 ...
PMID:Melanocortin-3 receptor mRNA expression in pro-opiomelanocortin neurones of the rat arcuate nucleus. 1084 78

The neuropeptides, monoamines and many drugs involved with modulating food intake and fat stores have reciprocal effects on sympathetic activity and thermogenesis. Both serotonin, acting through 5HT1B/2C receptors, and norepinephrine acting through beta2 and/or beta3 receptors reduce food intake and augment sympathetic activity. Neuropeptide Y, beta-endorphin, orexin, galanin and melanin concentrating hormone all increase food intake and, where tested, reduce sympathetic activity. In contrast, a larger number of peptides including cholecystokinin, corticotrophin-releasing hormone/urocortin, enterostatin, leptin, CART and alpha-MSH reduce food intake and increase sympathetic activity. Nicotine, prostaglandin, dexfenfluramine and sibutramine also have this reciprocal effect on feeding and sympathetic nervous system (SNS) activity. Chronic administration of neuropeptide Y (NPY) can produce chronically increased food intake and obesity. This syndrome is similar to the ventromedial hypothalamus (VMH) syndrome and suggests that NPY must be acting as an inhibitory signal to stimulate a feeding system and inhibit sympathetic activity. The melanocortin receptor system may be particularly important in modulating food intake, because a transgenic mouse which does not express melanocortin-4 receptors is massively overweight. Adrenal glucocorticoids are important in obesity since adrenalectomy will reverse or prevent the development of all forms of obesity. The clinical importance of the sympathetic nervous system and food intake is emphasized by the inverse relation of sympathetic activity and body fat. The inhibition of food intake, lower body fat stores and higher energy expenditure in smokers also support this hypothesis. The reciprocal relationship between food intake and sympathetic activity is robust, suggesting that beta receptors in the periphery and brain may be involved in the control of feeding and a reduction in food intake in humans accounts for most of the weight loss with ephedrine and caffeine. We conclude that the inhibition of feeding by activating the SNS is an important satiety system which helps regulate body fat stores.
 ...
PMID:Reciprocal relation of food intake and sympathetic activity: experimental observations and clinical implications. 1099

Adrenal glucocorticoid secretion is regulated by adrenocorticotropic hormone (ACTH) acting through a specific cell membrane receptor (ACTH-R). The ACTH-R is a member of the G protein superfamily-coupled receptors and belongs to the subfamily of melanocortin receptors. The ACTH-R is mainly expressed in the adrenocortical cells showing a restricted tissue specificity, although ACTH is recognized by the other four melanocortin receptors. The cloning of the ACTH-R was followed by the study of this gene in human diseases such as familial glucocorticoid deficiency (FGD) and adrenocortical tumors. FGD is a rare autosomal recessive disease characterized by glucocorticoid deficiency, elevated plasma ACTH levels and preserved renin/aldosterone secretion. This disorder has been ascribed to an impaired adrenal responsiveness to ACTH due to a defective ACTH-R, a defect in intracellular signal transduction or an abnormality in adrenal cortical development. Mutations of the ACTH-R have been described in patients with FGD in segregation with the disease. The functional characterization of these mutations has been prevented by difficulties in expressing human ACTH-R in cells that lack endogenous melanocortin receptor activity. To overcome these difficulties we used Y6 cells, a mutant variant of the Y1 cell line, which possesses a non-expressed ACTH-R gene allowing the functional study without any background activity. Our results demonstrated that the several mutations of the ACTH-R found in FGD result in an impaired cAMP response or loss of sensitivity to ACTH stimulation. An ACTH-binding study showed an impairment of ligand binding with loss of the high affinity site in most of the mutations studied.
 ...
PMID:The expression of the ACTH receptor. 1100 26

This review focuses on the expression, content, and release of neuropeptides and on their role in the development of obesity in animal models with single-gene mutations. The balance between neuropeptides that contribute to the control of feeding behavior is profoundly and variously altered in these models, supporting the concept of the existence of several types of obesity. The hypothalamic neuropeptide Y (NPY) and the pro-opiomelanocortin (POMC) systems are the networks most studied in relation to energy intake. Both receive information about the nutritional status and the level of energy storage through insulin and leptin signaling mediated by specific receptors located on POMC and NPY neurons present predominantly in the arcuate nucleus (ARC). When leptin signaling is defective, through a defect in either the receptor (Zucker fa/fa rat, cp/cp rat, and db/db mouse) or in the peptide itself (ob/ob mouse), the NPY system is upregulated as shown by mRNA overexpression and increased peptide release, whereas the content and/or release of some inhibitory peptides (neurotensin, cholecystokinin) are diminished. For the POMC system, there is a complex interaction between the tonic inhibition of food intake exerted by alpha-melanocyte-stimulating hormone (alpha-MSH) and the Agouti-related protein at the level of the type 4 melanocortin receptor. The latter peptide is coexpressed with NPY in the ARC. Corticotropin-releasing factor (CRF) is the link between food intake and environmental factors. It not only inhibits food intake and prevents weight gain, likely through hypothalamic effects, but also activates the hypothalamo-pituitary axis and therefore contributes to energy storage in adipose tissue. The factors that prod the CRF system toward the hypothalamic or hypothalamo-pituitary axis system remain to be more clearly defined (comodulators, connections between limbic system and ARC, cellular location, and type of receptors, etc. ). The pathways used by all of these neuromodulators include numerous brain areas, but some interest has returned to the classic ones such as the ventromedial and lateral hypothalamic areas because of the recent discovery of some peptides (orexins and melanin-concentrating hormone for the lateral hypothalamus) and receptors (CRF type 2 in the ventromedial hypothalamus). All of these pathways are redundant and function in a coordinated manner and sometimes by the novel expression of a peptide in an unusual area. The importance of such a phenomenon in obesity remains to be determined. Even if single-gene mutations are exceptions in human obesity, the study of genetic animal models of obesity has greatly contributed to the understanding of the regulation of feeding behavior and will allow researchers to develop new drug treatments for obesity that have to be associated with drastic changes in lifestyle (feeding, work habits, and physical activity) for a complete efficiency.
 ...
PMID:Neuropeptides and obesity. 1105 97

The presence and possible physiological roles of alpha-melanocyte-stimulating hormone (alpha-MSH) in the peripheral tissues of birds have not been established. By a combination of RT-PCR, immunocytochemistry and in situ hybridization, we have examined alpha-MSH expression in the eye of the chicken during development. In the 1-day-old chick, alpha-MSH was expressed in the retinal pigment epithelial (RPE) cells, and also at a lower level in the cone cells. The melanocortin receptor subtypes, CMC1, CMC4 and CMC5, were expressed in the layers of the choroid and the neural retina, but not in the RPE cells. It is probable that the RPE cells secrete alpha-MSH to exert paracrine effects on the choroid and neural retina. During embryonic development, alpha-MSH immunoreactivity in the RPE cells was initially detected at embryonic day 10, and increased in intensity as development proceeded. No cone cells were stained with anti-alpha-MSH antiserum in any of the embryonic stages tested. The immunoreactivities for two prohormone convertases, PC1 and PC2, were co-localized to the RPE cells with a pattern of staining similar to that of alpha-MSH. Despite containing alpha-MSH immunoreactivity, the RPE cells in 1-day-old chicks expressed no immunoreactivity for the endoproteases. Furthermore, in a 3-day-old chick, pro-opiomelanocortin mRNA was detectable by in situ hybridization only in the photoreceptor layer and not in the RPE cells. These results suggest that the RPE cells and the cone cells are intraocular sources of alpha-MSH in the embryonic and postnatal life of the chicken respectively. Embryonic expression of alpha-MSH in the RPE cells implies a possible role for the peptide in ocular development.
 ...
PMID:Identification of avian alpha-melanocyte-stimulating hormone in the eye: temporal and spatial regulation of expression in the developing chicken. 1124 Nov 84

Among various neuropeptides such as substance P, calcitonin gene-related peptide and others, alpha-melanocyte-stimulating hormone (alpha-MSH) was found to be produced in the skin. Moreover, melanocortin receptor 1 (MC-1R), which is specific for alpha-MSH and ACTH, is expressed in the skin on keratinocytes, dendritic cells, macrophages and endothelial cells. In monocytes, macrophages and dendritic cells alpha-MSH inhibits the production and activity of immunoregulatory and proinflammatory cytokines such as IL-2, IFN-gamma, TNF-alpha and IL-1. It downregulates the expression of costimulatory molecules such as CD86 and CD40 and induces the production of suppressor factors such as the cytokine synthesis inhibitory factor IL-10. On endothelial cells alpha-MSH is capable of downregulating the LPS-induced expression of adhesion molecules such as vascular cell adhesion molecule (VCAM) and E-selectin. Moreover, the LPS-induced activation of transcription factors such as NF kappa B is downregulated by alpha-MSH. In a mouse model i.v. or topical application of alpha-MSH was found to inhibit the induction phase as well as the effector phase of contact hypersensitivity (CHS) reactions and to induce hapten-specific tolerance. These findings indicate that the production of immunosuppressing neuropeptides such as alpha-MSH by epidermal cells may play an essential role during the pathogenesis of immune and inflammatory reactions in the skin.
 ...
PMID:The role of alpha-MSH as a modulator of cutaneous inflammation. 1126 49


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>