UNIPROT:P01189 - FACTA Search

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism by which ethanol induces beta-endorphin (beta-EP) neuronal death during the developmental period was determined using fetal rat hypothalamic cells in primary cultures. The addition of ethanol to hypothalamic cell cultures stimulated apoptotic cell death of beta-EP neurons by increasing caspase-3 activity. Ethanol lowered the levels of adenylyl cyclase (AC)7 mRNA, AC8 mRNA, and/or cAMP in hypothalamic cells, whereas a cAMP analog blocked the apoptotic action of ethanol on beta-EP neurons. The AC inhibitor dideoxyadenosine (DDA) increased cell apoptosis and reduced the number of beta-EP neurons, and it potentiated the apoptotic action of ethanol on these neurons. beta-EP neurons in hypothalamic cultures showed immunoreactivity to transforming growth factor-beta1 (TGF-beta1) protein. Ethanol and DDA increased TGF-beta1 production and/or release from hypothalamic cells. A cAMP analog blocked the activation by ethanol of TGF-beta1 in these cells. TGF-beta1 increased apoptosis of beta-EP neurons, but it did not potentiate the action of ethanol or DDA actions on these neurons. TGF-beta1 neutralizing antibody blocked the apoptotic action of ethanol on beta-EP neurons. Determination of TGF-beta1-controlled cell apoptosis regulatory gene levels in hypothalamic cell cultures and in isolated beta-EP neurons indicated that ethanol, TGF-beta1, and DDA similarly alter the expression of these genes in these cells. These data suggest that ethanol increases beta-EP neuronal death during the developmental period by cellular mechanisms involving, at least partly, the suppression of cAMP production and activation of TGF-beta1-linked apoptotic signaling.
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PMID:Ethanol induces apoptotic death of developing beta-endorphin neurons via suppression of cyclic adenosine monophosphate production and activation of transforming growth factor-beta1-linked apoptotic signaling. 1632 33

Adrenocorticotrophic hormone (ACTH(1-39)) and the melanocortins (alpha, beta and gamma-melanocyte-stimulating hormone [MSH]) are derived from a larger precursor molecule known as the pro-opiomelanocortin (POMC) protein. They exert their numerous biological effects by activating 7 transmembrane G-protein coupled receptors (GPCR), leading to adenylyl cyclase activation and subsequent cAMP accumulation within the target cell. To date, 5 melanocortin receptors (MCR) have been identified and termed MC1R to MC5R, they have been shown to have a wide and varied distribution throughout the body, being found in the central nervous system (CNS), periphery and immune cells. Melanocortins have a multitude of actions including: (i) modulating disease pathologies including arthritis, asthma, obesity; (ii) affecting functions, for example erectile dysfunction, skin tanning; and (iii) organ systems, for example cardiovascular system. Recently a mechanistic approach has been identified with alpha-MSH preventing NF-kappaB activation via the preservation and expression of IkappaBalphaprotein. This leads to a reduction of pro-inflammatory mediators including cytokines and inhibition of adhesion molecule expression, with subsequent reduction in leukocyte emigration. Development of selective ligands with an appropriate pharmacokinetic profile will enable a pharmacological evaluation of the potential beneficial effects of the melanocortins. In this review I have discussed the potential mechanistic action for the melanocortins and some of the disease pathologies shown to be modulated. This review proposes targeting the MCR with the ultimate aim of controlling many of the diseases that we face today.
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PMID:Targeting melanocortin receptors as potential novel therapeutics. 1648 18

The natural antimicrobial peptides are ancient host defense effector molecules, present in organisms across the evolutionary spectrum. Several properties of alpha-melanocyte stimulating hormone (alpha-MSH) suggested that it could be a natural antimicrobial peptide. Alpha-MSH is a primordial peptide that appeared during the Paleozoic era, long before adaptive immunity developed and, like natural antimicrobial molecules, is produced by barrier epithelia, immunocytes, and within the central nervous system. alpha-MSH was discovered to have antimicrobial activity against two representative pathogens, Staphylococcus aureus and Candida albicans. The candidacidal influences of alpha-MSH appeared to be mediated by increases in cell cyclic adenosine monophosphate (cAMP). The cAMP-inducing capacity of alpha-MSH likely interferes with the yeast's own regulatory mechanisms of this essential signaling pathway. It is remarkable that this mechanism of action in yeast mimics the influences of alpha-MSH in mammalian cells in which the peptide binds to G-protein-linked melanocortin receptors, activates adenylyl cyclase, and increases cAMP. When considering that most of the natural antimicrobial peptides enhance the local inflammatory reaction, the anti-inflammatory and antipyretic effects of alpha-MSH confer unique properties to this molecule relative to other natural antimicrobial molecules. Synthetic derivatives, chemically stable and resistant to enzymatic degradation, could form the basis for novel therapies that combine anti-inflammatory and antimicrobial properties.
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PMID:Antimicrobial properties of alpha-MSH and related synthetic melanocortins. 1702 69

Presynaptic receptors for four families of neuropeptides will be discussed: opioids, neuropeptide Y, adrenocorticotropic hormone (ACTH), and orexins. Presynaptic receptors for the opioids (micro, delta, kappa, and ORL(1)) and neuropeptide Y (Y(2)) inhibit transmitter release from a variety of neurones, both in the peripheral and central nervous systems. These receptors, which were also identified in human tissue, are coupled to G(i/o) proteins and block voltage-dependent Ca(2+) channels, activate voltage-dependent K(+) channels, and/or interfere with the vesicle release machinery. Presynaptic receptors for ACTH (MC(2) receptors) have so far been identified almost exclusively in cardiovascular tissues from rabbits, where they facilitate noradrenaline release; they are coupled to G(s) protein and act via stimulation of adenylyl cyclase. Presynaptic receptors for orexins (most probably OX(2) receptors) have so far almost exclusively been identified in the rat and mouse brain, where they facilitate the release of glutamate and gamma-aminobutyric acid (GABA); they are most probably linked to G(q) and directly activate the vesicle release machinery or act via a transduction mechanism upstream of the release process. Agonists and antagonists at opioid receptors owe at least part of their therapeutic effects to actions on presynaptic receptors. Therapeutic drugs targeting neuropeptide Y and orexin receptors and presynaptic ACTH receptors so far are not available.
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PMID:Presynaptic neuropeptide receptors. 1806 21

Cannabinoid receptor 2 (CB2) agonists provide the potential for treating chronic pain states without CNS effects associated with CB1 receptor activation. Animal models suggest that they act mainly via non-neuronal cells, possibly inhibition of inflammatory cells in the periphery or CNS, or via release of beta-endorphin; however, the clinical relevance and mechanism of analgesic action is uncertain. Here, we demonstrate colocalisation of CB2 with CB1 and the capsaicin receptor TRPV1 in human dorsal root ganglion (DRG) sensory neurons and increased levels of CB2 receptors in human peripheral nerves after injury, particularly painful neuromas. In primary cultures of human DRG neurons, selective CB2 agonists blocked activation of inward cation currents and elevation of cytoplasmic Ca2+ in response to capsaicin. These inhibitory effects were reversed by GW818646X a CB2 antagonist, and 8-bromo cAMP, but not by SR141716 a CB1 antagonist, or naloxone. Thus CB2 receptor agonists functionally inhibited nociceptive signalling in human primary sensory neurons via a mechanism shared with opioids, of adenylyl cyclase inhibition, but not via mu-opioid receptors. We conclude that CB2 agonists deserve imminent clinical trials for nociceptive, inflammatory and neuropathic chronic pain, in which capsaicin or heat-activated responses via TRPV1 may provide a clinical marker.
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PMID:Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons. 1869 62

Melanocortin 5 receptor (MC5R) is a G protein coupled receptor (GPCR) with high affinity for alpha-melanocyte-stimulating hormone (alpha-MSH). To unravel some of the downstream cell-signaling pathways activated by this receptor, HEK293 cells were transiently and stably transfected with a vector encoding green fluorescent protein (GFP)-tagged MC5R. In these cells the receptor was correctly addressed to the cell surface and was functional, as shown by the MC5R-induced formation of intracellular cAMP. In fact, the MC5R agonist alpha-MSH induced a 10- or 16-fold increase (transient or stable cells, respectively) above the cAMP levels found in unstimulated cells. Moreover, in cells stably expressing MC5R-GFP, alpha-MSH promoted ERK1/2 phosphorylation in a dose-dependent manner (EC50=7.3 nM) with the maximal effect occurring after 5 min of agonist incubation. The signaling pathway conveyed through ERK1/2 is not linked to cAMP, since the phosphorylation of these kinases is unchanged by the inhibition of adenylyl cyclase. Also, ERK1/2 activation is not significantly affected by protein kinase A (PKA), protein kinase C (PKC) and protein kinase B or Akt (Akt/PKB) specific inhibitors. However, alpha-MSH-induced ERK1/2 activation is abolished by the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002. Altogether, these findings demonstrate that MC5R signals through a PI3K-regulated Akt-independent pathway leading to downstream activation of ERK1/2. The involvement of these MAPK suggests that MC5R could be implicated in cellular proliferation or differentiation mechanisms.
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PMID:Melanocortin 5 receptor activates ERK1/2 through a PI3K-regulated signaling mechanism. 1942 94

Melanin granule (melanosome) dispersion within Xenopus laevis melanophores is evoked either by light or alpha-MSH. We have previously demonstrated that the initial biochemical steps of light and alpha-MSH signaling are distinct, since the increase in cAMP observed in response to alpha-MSH was not seen after light exposure. cAMP concentrations in response to alpha-MSH were significantly lower in cells pre-exposed to light as compared to the levels in dark-adapted melanophores. Here we demonstrate the presence of an adenylyl cyclase (AC) in the Xenopus melanophore, similar to the mammalian type IX which is inhibited by Ca(2+)-calmodulin-activated phosphatase. This finding supports the hypothesis that the cyclase could be negatively modulated by a light-promoted Ca(2+) increase. In fact, the activity of calcineurin PP2B phosphatase was increased by light, which could result in AC IX inhibition, thus decreasing the response to alpha-MSH. St-Ht31, a disrupting agent of protein kinase A (PKA)-anchoring kinase A protein (AKAP) complex totally blocked the melanosome dispersing response to alpha-MSH, but did not impair the photo-response in Xenopus melanophores. Sequence comparison of a melanophore AKAP partial clone with GenBank sequences showed that the anchoring protein was a gravin-like adaptor previously sequenced from Xenopus non-pigmentary tissues. Co-immunoprecipitation of Xenopus AKAP and the catalytic subunit of PKA demonstrated that PKA is associated with AKAP and it is released in the presence of alpha-MSH. We conclude that in X. laevis melanophores, AKAP12 (gravin-like) contains a site for binding the inactive PKA thus compartmentalizing PKA signaling and also possesses binding sites for PKC. Light diminishes alpha-MSH-induced increase of cAMP by increasing calcineurin (PP2B) activity, which in turn inhibits adenylyl cyclase type IX, and/or by activating PKC, which phosphorylates the gravin-like molecule, thus destabilizing its binding to the cell membrane.
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PMID:Light modulates the melanophore response to alpha-MSH in Xenopus laevis: an analysis of the signal transduction crosstalk mechanisms involved. 1953 25

While stress is known to impact reproductive performance, the pathways involved are not entirely understood. Corticosteroid effects on the functioning of the hypothalamus-pituitary-gonadal axis are thought to be a key aspect of stress-mediated reproductive dysfunction. A vital component of the stress response is the pituitary secretion of adrenocorticotropic hormone (ACTH), which binds to the melanocortin 2 receptor (MC2R) in the adrenal glands and activates cortisol biosynthesis. We recently reported MC2R mRNA abundance in fish gonads leading to the hypothesis that ACTH may be directly involved in gonadal steroid modulation. Using zebrafish (Danio rerio) ovarian follicles, we tested the hypothesis that acute ACTH stimulation modulates cortisol and estradiol (E(2)) secretion. ACTH neither affected cortisol nor unstimulated E(2) release from ovarian follicles. However, ACTH suppressed human chorionic gonadotropin (hCG)-stimulated E(2) secretion in a dose-related manner, with a maximum decrease of 62% observed at 1 I.U. ACTH mL(-1). This effect of ACTH on E(2) release was not observed in the presence of either 8-bromo-cAMP or forskolin, suggesting that the mechanism(s) involved in steroid attenuation was upstream of adenylyl cyclase activation. Overall, our results suggest that a stress-induced rise in plasma ACTH levels may initiate a rapid down-regulation of acute stimulated E(2) biosynthesis in the zebrafish ovary, underscoring a novel physiological role for this pituitary peptide in modulating reproductive activity.
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PMID:Adrenocorticotropic hormone suppresses gonadotropin-stimulated estradiol release from zebrafish ovarian follicles. 1964 43

We tested the hypothesis that single and repeated immobilization stress affect densities of alpha(1)-adrenoceptor (alpha(1)-AR) and beta-AR subtypes, muscarinic receptors (MR), adenylyl cyclase activity (AC) and phospholipase C activity (PLC) in lungs of male and female wild type (WT) and corticotropin-releasing hormone gene (CRH-knockout (KO)) disrupted mice. We found sex differences in the basal levels of alpha(1)-AR subtypes (females had 2-3 times higher density of receptors than males) and MR (males had twice the density found in females). In marked contrast, beta-AR subtype densities did not differ between sexes. CRH gene disruption decreased all three studied receptors in intact mice (to 20-50% of WT) in both sexes (except beta(1)-AR in females). Stress induced sexually dimorphic responses, while all alpha(1)-AR subtypes decreased in females (to 30% of control approximately), only alpha(1A)-AR level diminished (about 50%) in males. beta(1)-AR decreased in males (to about 40%) but remained stable in females. beta(2)-AR diminished in females (to about 20-60%) and also in males (to about 30-60%). MR decreased in both sexes (approximately to 50%). AC activity diminished in males (to < 50%) while PLC activity was not changed. In CRH-KO mice, the stress response was severely diminished. Paradoxically, the receptor response to stress was less affected by CRH-KO in males than in females. AC activity did not change in CRH-KO mice. In conclusion, in mice the stress reaction is sexually dimorphic and an intact hypothalamo-pituitary-adrenocortical system is required for the normal reaction of pulmonary adrenergic and MR to stress.
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PMID:Sexual dimorphism in stress-induced changes in adrenergic and muscarinic receptor densities in the lung of wild type and corticotropin-releasing hormone-knockout mice. 2010 53

Although ethanol has been considered to be an anxiolytic agent, consumption of ethanol has also been shown to increase plasma adrenocorticotropin and glucocorticoids. The corticotrophin-releasing factor (CRF) receptor 1alpha (CRF-R1) is a G protein-coupled receptor that activates adenylyl cyclase (AC), leading to adrenocorticotropin (and subsequently glucocorticoid) release into the circulation. There are nine members of the membrane-bound AC family, and the type 7 AC (AC7) is most sensitive to ethanol, which enhances the responsiveness of AC7 to G protein-coupled receptor activation. We determined the time course of ethanol's effect on plasma adrenocorticotropin and corticosterone levels in male and female AC7 transgenic (Adcy7(huTG)) mice (in which AC7 is overexpressed in neural tissue) and AC7 heterozygous knockdown [Adcy7(+/-)] mice (in which AC7 is underexpressed in neural tissue), and their respective littermate controls [wild type (WT)]. CRF-R1 mRNA and mRNA and protein for different forms of ACs were measured by using gene expression arrays, quantitative reverse transcription-polymerase chain reaction, and immunoblotting in pituitaries of all animals. Our results demonstrated increased levels of AC7 in pituitary of Adcy7(huTG) mice and decreased levels in pituitary of Adcy7(+/-) mice compared with WT animals. Male and female Adcy7(huTG) mice displayed higher plasma adrenocorticotropin and corticosterone levels than WT and/or Adcy7(+/-) mice after ethanol injection. Female mice displayed higher adrenocorticotropin and corticosterone levels after ethanol injection than males, regardless of genotype. The data provide evidence for an integral role of AC7 in the increase of plasma adrenocorticotropin and corticosterone levels during alcohol intoxication.
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PMID:Type 7 adenylyl cyclase-mediated hypothalamic-pituitary-adrenal axis responsiveness: influence of ethanol and sex. 2036 52

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