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)

The purpose of this study was to determine whether or not vasopressin release in response to various stimuli in the conscious rat is controlled by endogenous opioid peptides, in particular beta-endorphin. Naloxone (1 mg.kg-1 i.m.) promoted vasopressin release in response to both an angiotensin II infusion (500 ng . kg-1 . min-1) or an isosmolar, nonhypotensive hypovolaemia achieved by polyethylene glycol injection (PEG, 20% solution i.p.); however, naloxone was without effect when vasopressin release was induced by hypertonic saline injection (2.5% solution i.p.) or a severe fall in arterial blood pressure following trimethidinium (10 mg . kg-1 i.m.) induced ganglionic blockade. Vasopressin release was accompanied by an increase in plasma beta-endorphin-like immunoreactivity (beta-EI) following an angiotensin II infusion of PEG administration, but not after hypertonic saline or trimethidinium injection. Dexamethasone pretreatment (0.5 mg . kg-1 twice i.p.) prevented the increase in plasma beta-EI following an angiotensin II infusion or PEG administration. The simultaneous angiotensin II- or PEG-induced increase in vasopressin release was unaffected or potentiated, respectively, by the glucocorticoid. In contrast, vasopressin release in response to hypertonic saline or trimethidinium injection was significantly inhibited by dexamethasone. We conclude that an inhibitory control by endogenous opiates is involved in some, but not all of the different pathways leading to vasopressin release. The results obtained do not prove but can be reconciled with the proposal that hypophyseal beta-endorphin is the compound responsible.
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PMID:Vasopressin and beta-endorphin release after osmotic and non-osmotic stimuli: effect of naloxone and dexamethasone. 627 72

The possibility that divalent cations may antagonize opiate peptide analgesia and stress-induced analgesia was examined. Intracerebroventricular injection of low doses of Ca2+, Mn2+ and Mg2+ antagonized beta-endorphin and methionine-enkephalin analgesia. Ba2+ and Cd2+ were without effect. The ionophore, A23187, significantly antagonized beta-endorphin analgesia and the effect was increased when a low dose of Ca2+ was injected at the same time as the ionophore. Ethylene glycol tetraacetic acid (but not ethylenediamine tetraacetic acid) significantly potentiated endorphin analgesia. Stress-induced analgesia, as determined by increased tail-flick latencies following intraperitoneal injection of acetic acid, was effectively antagonized by naloxone, Ca2+ and Mn2+. The frequency of writhing following acetic acid injection was increased by both naloxone and divalent metal ions, again suggesting antagonism of endogenous opiates. These results confirm previous findings indicating that divalent metal ions (and especially Ca2+) may be involved in the actions of opiates.
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PMID:Modification of endorphin/enkephalin analgesia and stress-induced analgesia by divalent cations, a cation chelator and an ionophore. 682 Nov 93

In the present study, we used subcutaneous polyethylene glycol injections to show that a physiologically relevant stimulus, hypovolemia, will selectively increase the expression of neuropeptide genes in a restricted population of parvicellular corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Our results show that a large reduction in extracellular fluid maintained over approximately 20 hours is associated with a significant increase in the level of corticotropin-releasing hormone mRNA in the medial parvicellular division of the paraventricular nucleus. Additionally, there are concomitant increases in cellular levels of both neurotensin/neuromedin N and proenkephalin mRNAs. Our colocalization results show that the increases in neurotensin/neuromedin N and proenkephalin mRNAs after polyethylene glycol injection occur to a significant degree in cells that also contain corticotropin-releasing hormone mRNA. Furthermore, significant numbers of cells containing proenkephalin mRNA also contain neurotensin/neuromedin N mRNA, raising the possibility that some neurons have increased levels of all three mRNAs. Finally, in the medial parvicellular division of the paraventricular nucleus, the number of identified corticotropin-releasing hormone neurons also containing vasopressin mRNA is very low in control animals and is not increased by polyethylene glycol injections, suggesting that, within this period, activation of the vasopressin gene may not be a critical event in the neuroendocrine response of corticotropin-releasing hormone neurosecretory neurons to extracellular dehydration. Considered together with the effects of adrenalectomy on peptide colocalization, our results suggest the existence of several phenotypically distinct sets of neurons within the medial parvicellular division of the paraventricular nucleus, each characterized by its ability to regulate the expression of neuropeptide genes in a stimulus-specific manner.
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PMID:Physiological regulation of peptide messenger RNA colocalization in rat hypothalamic paraventricular medial parvicellular neurons. 772 97

An analogue of human melanin-concentrating hormone (MCH) suitable for radioiodination was designed in which Tyr13 and Val19 of the natural peptide were replaced by phenylalanyl and tyrosyl residues: [Phe13, Tyr19]-MCH. The peptide was synthesized by the continuous-flow solid-phase methodology using Fmoc-strategy and polyhipe PA 500 and PEG-PS resins. The linear MCH peptides with either acetamidomethyl-protected or free cysteinyl residues were purified to homogeneity and cyclized by iodine oxidation, yielding the final product with the correct molecular weight of 2434.61. Radioiodination of the C-terminal tyrosine was carried out enzymatically using solid-phase bound glucose oxidase/lactoperoxidase, followed by purification on a reversed-phase mini-column and by high-pressure liquid chromatography. The resulting [125I]-[Phe13, Tyr19]-MCH tracer was the first radiolabelled MCH peptide suitable for radioreceptor assay: saturation binding analysis using mouse G4F-7 melanoma cells demonstrated the presence of 1090 MCH receptors per cell. The dissociation constant (KD) was 1.18 x 10(-10) M, indicating high-affinity MCH receptors on these cells. MCH receptors were also found in other cell lines such as mouse B16-F1 and G4F and human RE melanoma cells as well as in PC12 and COS-7 cells. Competition binding analyses with a number of other peptides such as alpha-MSH, neuropeptide Y, substance P and pituitary adenylate cyclase activating peptide, demonstrated that the binding to the MCH receptor is specific. Atrial natriuretic factor was found to be a weak competitor of MCH, indicating topological similarities between MCH and ANF when interacting with MCH receptors.
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PMID:Synthesis and iodination of human (phenylalanine 13, tyrosine 19) melanin-concentrating hormone for radioreceptor assay. 922 84

A photoreactive analogue of human melanin-concentrating hormone was designed, [D-Bpa13,Tyr19-MCH, containing the D-enantiomer of photolabile p-benzoylphenylalanine (Bpa) in position 13 and tyrosine for radioiodination in position 19. The linear peptide was synthesized by the continuous-flow solid-phase methodology using Fmoc-strategy and PEG-PS resins, purified to homogeneity and cyclized by iodine oxidation. Radioiodination of [D-Bpa13,Tyr19]-MCH at its Tyr19 residue was carried out enzymatically using solid-phase bound glucose oxidase/lactoperoxidase, followed by purification on a reversed-phase mini-column and HPLC. Saturation binding analysis of [125I]-[D-Bpa13,Tyr19]-MCH with G4F-7 mouse melanoma cells gave a K(D) of 2.2+/-0.2 x 10(-10) mol/l and a B(max) of 1047+/-50 receptors/cell. Competition binding analysis showed that MCH and rANF(1-28) displace [125I]-[D-Bpa13,Tyr19]-MCH from the MCH binding sites on G4F-7 cells whereas alpha-MSH has no effect. Receptor crosslinking by UV-irradiation of G4F-7 cells in the presence of [125I]-[D-Bpa13,Tyr19]-MCH followed by SDS-polyacrylamide gel electrophoresis and autoradiography yielded a band of 45-50 kDa. Identical crosslinked bands were also detected in B16-F1 and G4F mouse melanoma cells, in RE and D10 human melanoma cells as well as in COS-7 cells. Weak staining was found in rat PC12 phaeochromocytoma and Chinese hamster ovary cells. No crosslinking was detected in human MP fibroblasts. These data demonstrate that [125I]-[D-Bpa13,Tyr19]-MCH is a versatile photocrosslinking analogue of MCH suitable to identify MCH receptors in different cells and tissues; the MCH receptor in these cells appears to have the size of a G protein-coupled receptor, most likely with a varying degree of glycosylation.
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PMID:(D-(p-benzoylphenylalanine)13, tyrosine19)-melanin-concentrating hormone, a potent analogue for MCH receptor crosslinking. 1036 6

Beta-endorphin is the largest natural opioid peptide. The knowledge of its bioactive conformation might be very important for the indirect mapping of the active site of opioid receptors. We have studied beta-endorphin in a variety of solution conditions with the goal of testing the intrinsic tendency of its sequence to assume a regular fold. We ran NMR experiments in water, dimethylsulfoxide and aqueous mixtures of methanol, ethylene glycol, trifluoroethanol, hexafluoracetone trihydrate and dimethylsulfoxide. The solvent in which the peptide is more ordered is the hexafluoracetone trihydrate/water mixture. The helical structure detected for beta-endorphin in this mixture at 300 K extends for the greater part of its address domain, hinting at a possible mechanism of interaction with opioid receptors: a two-point attachment involving an interaction of the helical part of the address domain (PLVTLFKNAIIKNAY) with one of the transmembrane helices and a classical interaction of the message domain (YGGF) with the receptor subsite common to all opioid receptors.
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PMID:Solution structure of human beta-endorphin in helicogenic solvents: an NMR study. 1052 84

Rat liver nucleotide pyrophosphatase/phosphodiesterase I (NPP/PDE) catalysed efficiently the transfer of adenylate from ATP to alcohols (methanol, ethanol, propanol, ethylene glycol, glycerol, 2, 2-dichloroethanol and glycerol 2-phosphate), which acted as adenylate acceptors competing with water with different efficiencies. NPP/PDE kinetics in alcohol/water mixtures were accounted for by rate equations for competitive substrates, modified to include alcohol negative co-operativity and, depending on the nature of the alcohol, enzyme denaturation by high alcohol concentrations or activation by low alcohol concentrations. The correlation of alcohol efficiencies with alcohol acidities, the comparison of rat liver with snake venom NPP/PDE, and the different effects of ionic additives on the efficiencies of glycerol 2-phosphate and glycerol provided evidence for interaction of the alcohols with a base catalyst, a non-polar and a cationic subsite in the active centre of rat liver NPP/PDE. The enzyme thus appears to be well suited to act as transferase, and we propose that NPP/PDE could be an adenylylating agent in the membrane.
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PMID:Rat liver nucleotide pyrophosphatase/phosphodiesterase is an efficient adenylyl transferase. 1065 35

Poly(ethylene glycol), or PEG, conjugation to proteins and peptides is a growing technology used to enhance efficacy of therapeutics. This investigation assesses pharmacodynamic and pharmacokinetic characteristics of PEG-conjugated [D-Pen2,D-Pen5]-enkephalin (DPDPE), a met-enkephalin analog, in rodent (in vivo, in situ) and bovine (in vitro) systems. PEG-DPDPE showed increased analgesia (i.v.) compared with nonconjugated form (p < 0.01), despite a 172-fold lower binding affinity for the delta-opioid receptor. [125I]PEG-DPDPE had a 36-fold greater hydrophilicity (p < 0.01) and 12% increase in the unbound plasma protein fraction (p < 0.01), compared with [(125)I]DPDPE. [125I]PEG-DPDPE had a 2.5-fold increase in elimination half-life (p < 0.01), 2.7-fold decrease in volume of distribution (p < 0.01), and a 7-fold decrease in plasma clearance rate (p < 0.01) to [125I]DPDPE. Time course distribution showed significant concentration differences (p < 0.01) in plasma, whole blood, liver, gallbladder, gastrointestinal (GI) content, GI tract, kidneys, spleen, urine, and brain (brain, p < 0.05), between the conjugated and nonconjugated forms. Increased brain uptake of [(125)I]PEG-DPDPE corresponded to analgesia data. [125I]PEG-DPDPE in brain was shown to be 58.9% intact, with 41.1% existing as [125I]DPDPE (metabolite), whereas [125I]DPDPE was 25.7% intact in the brain (at 30 min). In vitro P-glycoprotein affinity was shown for [125I]DPDPE (p < 0.01) but not shown for [125I]PEG-DPDPE. In vitro saturable uptake, with 100 microM DPDPE, was shown for [125I]PEG-DPDPE (p < 0.05). In this study, PEG-conjugated DPDPE seems to act as a prodrug, enhancing peripheral pharmacokinetics, while undergoing hydrolysis in the brain and allowing nonconjugated DPDPE to act at the receptor.
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PMID:Pharmacodynamic and pharmacokinetic characterization of poly(ethylene glycol) conjugation to met-enkephalin analog [D-Pen2, D-Pen5]-enkephalin (DPDPE). 1145 51

Although the convergence of neural and humoral afferent information onto paraventricular neuroendocrine corticotropin-releasing hormone (CRH) neurons is a major determinant for adaptive stress responses, the underlying integrative mechanisms are poorly understood. To dissect the relative contributions made by neural afferents and corticosterone to these processes, we determined how the concurrent application of two heterotypic physiological stressors, chronic dehydration (produced by drinking hypertonic saline) and sustained hypovolemia (produced by subcutaneous injections of polyethylene glycol), is interpreted by the synthetic and secretory activity of CRH neurons using in situ hybridization and plasma ACTH measurements. These two stressors are encoded by relatively simple, distinct, and well defined sets of neural afferents to CRH neurons. Both increase plasma corticosterone, but they have opposing actions on CRH gene expression when applied separately. In the first experiment, we showed that chronic dehydration suppresses CRH gene transcription after hypovolemia, but not the preproenkephalin and c-fos mRNA responses or ACTH secretion. In the second, we showed that negative feedback actions of corticosterone do not suppress CRH gene activation after hypovolemia, but instead determine the prestress lower limit of a range within which the CRH gene then responds. Collectively, these data show that at least two processes are integrated to control how the CRH gene responds to multiple stimuli. First, the presence of corticosterone, which although permissive for appropriately activating the CRH gene during hypovolemia, does not mediate the suppressed gene response. Second, neural afferent-driven processes that encode dehydration play a central role in suppressing CRH activation.
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PMID:Interactions between heterotypic stressors and corticosterone reveal integrative mechanisms for controlling corticotropin-releasing hormone gene expression in the rat paraventricular nucleus. 1212 87

This study was designed to examine the role of opioids in cell survival, with an emphasis on the mechanism of opioid growth factor (OGF, [Met(5)]-enkephalin)-dependent growth inhibition. Using three human cancer cell lines: MIA PaCa-2 pancreatic adenocarcinoma, HT-29 colon adenocarcinoma, and CAL-27 squamous cell carcinoma of the head and neck, and OGF and the opioid antagonist naltrexone (NTX) at a dosage (10(-6)M) selected because it is known to repress or increase, respectively, cell replication, the effects on apoptosis (TUNEL, Annexin V) and necrosis (trypan blue) were investigated on days 2, 5, and 7 of exposure. In addition, the influence of a variety of other natural and synthetic opioids on apoptosis and necrosis was examined at a dosage of 10(-6)M. OGF, NTX, naloxone, [D-Pen(2,5)]-enkephalin, [Leu(5)]-enkephalin, dynorphin A1-8, beta-endorphin, endomorphin-1 and -2, and methadone at concentrations of 10(-6)M did not alter cell viability of any cancer cell line. Exposure of cultures to [D-Ala(2),MePhe(4),Glycol(5)]-enkephalin (DAMGO), morphine, or etorphine at 10(-6)M significantly increased the number of adherent cells positively stained for TUNEL and Annexin V, as well as the number of necrotic cells in the supernatant, from control levels at all time points studied. The effects of DAMGO, morphine, and etorphine on apoptosis/necrosis were not fully blocked by concomitant administration of naloxone. Despite the increase in cell death in some opioid-treated groups, the number of apoptotic and necrotic adherent cells, and the number of necrotic cells in the supernatant, was no more than 1-2% of the total cell population. These results indicate that the inhibitory (OGF) or stimulatory (NTX) action on cell growth in tissue culture is not due to alterations in apoptotic or necrotic pathways. Moreover, although some opioids increased cell death, and dose-effect relationships need to be established, this activity was not of great magnitude and supports the previously reported lack of growth inhibition of many of these compounds.
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PMID:Opioids and the apoptotic pathway in human cancer cells. 1274 39


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