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)

We recently showed that the opioid alkaloids, etorphine, dihydroetorphine and diprenorphine, have remarkably potent antagonist actions on excitatory opioid receptor functions in mouse sensory dorsal root ganglion (DRG) neurons. Pretreatment of naive nociceptive types of neurons with pM concentrations of these antagonists blocks excitatory prolongation of the calcium-dependent component of the action potential duration (APD) elicited by pM-nM morphine or other bimodally acting mu, delta and kappa opioid agonists and unmasks inhibitory APD shortening which usually requires much higher (ca. microM) concentrations. The present study demonstrates that pM concentrations of [des-Tyr1] fragments of dynorphin and beta-endorphin, as well as beta-endorphin-(1-27), can also selectively block excitatory opioid receptor functions in DRG neurons and unmask potent inhibitory effects of low concentrations of bimodally acting mu, delta and kappa opioid peptides and alkaloid agonists. These N- or C-terminus modified dynorphin or beta-endorphin peptides can be readily formed in neurons by specific peptidase activities. Since sustained activation of excitatory opioid receptor functions is essential for the development of tolerance/dependence in chronic morphine-treated DRG neurons in culture, the present in vitro study may help to account for the unexplained efficacy of [des-Tyr1] dynorphin fragments, as well as the endogenous opioids dynorphin A and beta-endorphin, in suppressing development and expression of naloxone-precipitated withdrawal and morphine tolerance in vivo.
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PMID:Specific N- or C-terminus modified dynorphin and beta-endorphin peptides can selectively block excitatory opioid receptor functions in sensory neurons and unmask potent inhibitory effects of opioid agonists. 775 76

The effects of a mixture of three peptidase inhibitors (PIs), amastatin, captopril and phosphoramidon, on methionine-enkephalin (Met-enk)-, beta-endorphin (beta-end)-, dynorphin-(1-13) (Dyn)- and electroacupuncture (EA)-induced antinociception were compared in rats. EA was performed by passing electric pulses (3 Hz, 0.1-msec duration, for 45 min) through acupuncture needles inserted into the Hoku-point. The antinociceptive effect was estimated by the hind paw pressure test. The antinociceptive effects of Met-enk and beta-end injected i.c.v. or i.t. and of Dyn injected i.t. were clearly potentiated by the PIs pretreated by the same administration routes as used for the injection of opioid peptides. The antinociceptive effects of Met-enk, beta-end and Dyn injected i.c.v. were also potentiated significantly by i.t.-PIs. PIs injected into the periaqueductal gray (PAG) potentiated EA antinociception. However, the EA effect was not affected by i.t.-PIs and was rather attenuated by i.c.v.-PIs. These results suggest that: i) Met-enk hydrolyzing enzymes are involved in the degradation of not only Met-enk but also beta-end and Dyn in the rat central nervous system; ii) Met-enk and beta-end act on both supraspinal and spinal sites, while Dyn acts only on the spinal site; iii) EA antinociception is mediated by supraspinal Met-enk and/or beta-end; and iv) an anti-opiate peptide system may be activated by EA stimulation, being susceptible to Met-enk hydrolyzing enzymes.
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PMID:Effects of a mixture of peptidase inhibitors (amastatin, captopril and phosphoramidon) on Met-enkephalin-, beta-endorphin-, dynorphin-(1-13)- and electroacupuncture-induced antinociception in rats. 786 21

Met-enkephalin is known to circulate in human and animal plasma in low levels. However, the source(s) of plasma met-enkephalin have not been completely elucidated. It has been proposed that the adrenal gland, sympathetic nerves, pancreas and the gut might be implicated. Recently, markedly elevated levels of met-enkephalin have been documented in the presence of liver disease. To investigate potential sources of met-enkephalin in liver disease, rats with acute cholestatic hepatitis 24 h after gavage with alpha naphthylisothiocyanate (ANIT) 100 mg/kg were studied. Plasma met-enkephalin levels were determined by radioimmunoassay in plasma samples from normal, adrenalectomized, or chemically sympathectomized animals. In control rats, ANIT treatment resulted in a striking 8.7-fold increase in systemic venous met-enkephalin levels (inferior vena cava) (P < or = 0.0005) and a significant increase in peptidase-derived met-enkephalin levels (determined after trypsin/carboxypeptidase B digestion of plasma samples) (P < or = 0.05). ANIT-treatment also resulted in a 5.6-fold increase in portal vein met-enkephalin levels (P < or = 0.005). Portal vein met-enkephalin levels were only 1.2-fold higher than IVC levels in ANIT-treated rats (P < or = 0.05). Plasma activities of the two main enkephalin degrading enzymes, aminopeptidase and enkephalinase, were similar in control and ANIT-treated rats. Chemical sympathectomy, prior to ANIT treatment, decreased the elevation in inferior vena caval met-enkephalin levels by 35% (P < or = 0.005). Adrenalectomy did not alter ANIT-induced increases in circulating met-enkephalin levels (pNS).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sympathetic nerves, but not the adrenal gland, contribute to elevated plasma levels of met-enkephalin in rats with acute cholestatic hepatitis. 821 May 12

Peptides function as chemical signals between cells of multicellular organisms, or different organisms, via specific receptors on target cells. Many hormones, neuromodulators, and growth factors are peptides. Because there is no known reuptake system for peptides at the nerve terminal, the biological activity of peptides in the extracellular space is regulated by enzymatic degradation and extracellular metabolism. For example, angiotensin I is processed extracellularly in the lung by angiotensin-converting enzyme (ACE; E.C. 3.4.15.1), a peptidyl dipeptidase, to form the potent vasoconstrictor hormone angiotensin II. When neuropeptides are released from neurons into the extracellular space, specific peptidases also can modulate the peptidergic signal by generating smaller, biologically active fragments via products with similar or dissimilar characteristics of the parent peptide. Therefore, receptor-binding selectivity of a released peptide hormone can be regulated by peptidases. Because peptidases may play a key role in the extracellular regulation of peptidergic signaling, alterations in peptidase activities by drugs or disease states may lead to disruptions in biological homeostasis. The subject of this article is the role of peptidases in the central nervous system in the formation of biologically active, receptor-specific peptides from peptide E, beta-endorphin, neurotensin, and cholecystokinin.
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PMID:Peptidases in the CNS: formation of biologically active, receptor-specific peptide fragments. 822 10

Pharmacological evidence for the existence of delta-opioid receptor subtypes has been reported. This study was conducted to determine which type of delta-opioid receptors was involved supraspinally and spinally when antinociception was induced by the natural enkephalins, [Leu5]enkephalin and [Met5]enkephalin. In the mouse tail flick assay, the antinociceptive ED50 values of both intracerebroventricularly (i.c.v.) administered [Leu5]enkephalin and [Met5]enkephalin (together with the peptidase inhibitors, bestatin and thiorphan) were significantly increased by 7-benzylidenenaltrexone (BNTX), a selective delta 1-opioid receptor antagonist but not by naltriben, a selective delta 2-opioid receptor antagonist. On the other hand, when the enkephalins were administered intrathecally (i.t.), the antinociceptive ED50 values of both enkephalins were significantly raised by naltriben but not by BNTX. beta-Endorphin-induced (i.c.v.) antinociception was antagonized by naltriben administered i.t. or s.c. but not by BNTX administered i.t. or s.c. Different delta-opioid receptor subtypes appeared to be involved in supraspinal (delta 1) and spinal (delta 2) antinociception induced by endogenous delta-opioid receptor agonists, [Leu5] and [Met5]enkephalin. The antinociception produced by i.c.v. administered beta-endorphin has been attributed to the release of [Met5]enkephalin in the spinal cord and its antagonism by naltriben support the finding that enkephalins interact with delta 2-opioid receptors in the spinal cord to mediate antinociception. beta-Endorphin may be interacting at receptors other than delta 1- or delta 2-opioid receptors in the brain, perhaps the putative epsilon receptors, to mediate their effects because neither i.c.v. administered BNTX nor naltriben inhibited its activity.
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PMID:Enkephalin antinociception in mice is mediated by delta 1- and delta 2-opioid receptors in the brain and spinal cord, respectively. 825 11

Palpable breast cysts with an apocrine epithelial lining (type 1) are reported to be associated with a higher risk of developing breast cancer. The composition of breast cyst fluid (BCF) might include those factors involved in this increased risk. In this study peptidase activities that were active against the substrate [125I]metenkephalin-Arg-Phe were detected in BCF. The products were identified by reversed phase high-performance liquid chromatography (HPLC) as [125I]Tyr-Gly-Gly and [125I]Met-enkephalin. This proteolysis was not inhibited by PCMB, pepstatin A, leupeptin or aprotinin but was by EDTA, showing that the activity was due to metalloproteases. The production of [125I]Try-Gly-Gly was inhibited by phosphoramidon and thiorphan, whereas that of [125I]met-enkephalin was inhibited by captopril and Bothrops jararaca peptide, indicating that these activities are enkephalinase and angiotensin-converting enzyme (ACE) respectively. A fluorometric assay for ACE demonstrated that ACE levels are significantly higher in type 2 BCF than in type 1 BCF (30.8 vs 6.1 nmol hr-1 10 microliters-1, P < 0.001). As the increased risk of cancer is linked to type 1 cysts it is possible that higher levels of peptidase in type 2 BCF reflect a protective environment in the breast in which mitogenic peptide growth factors are neutralised by proteolysis.
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PMID:Angiotensin-converting enzyme and enkephalinase in human breast cyst fluid. 879 86

Beta-endorphin metabolism by CD4+ and CD8+ T cells, and the thymoma cell line, EL4, was investigated. In all three cell types, extracellular beta-endorphin was metabolized exclusively by a secreted, metal-dependent, thiol peptidase. The enzyme activity is expressed constitutively in EL4 cells and following activation of CD4+ and CD8+ T cells with anti-CD3 antibody. The enzyme is not one of the proteinases associated with cytolytic T cells and does not appear to be identical with any previously described beta-endorphin metabolizing enzyme. The enzyme cleaves beta-endorphin at approximately equal rates at either of two sites to yield beta-endorphin(1-17) (which is gamma-endorphin), beta-endorphin(1-18), beta-endorphin(18-31) and beta-endorphin(19-31). Evidence in the literature indicates that these N- and C-terminal peptides which contain, respectively, the opioid and non-opioid receptor binding domains of beta-endorphin, are biologically active. Thus, it is likely that this new T cell peptidase has important immunoregulatory activity.
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PMID:A secreted peptidase involved in T cell beta-endorphin metabolism. 886 41

The EL-4 thymoma cell line contains a peptidase which converts beta-endorphin to beta-endorphin 1-17 (gamma-endorphin), beta-endorphin 1-18, and their corresponding C-terminal fragments. This enzyme was purified approximately 700-fold to a single band on an SDS-polyacrylamide gel (106 kDa) in 16% yield. Estimation of the native molecular weight by molecular sieve chromatography gave a value of approximately 220 kDa, indicating that this enzyme is a dimer. Peptide sequencing demonstrated this activity can be attributed to insulin degrading enzyme, a previously described member of the inverzincin family (Hooper, 1994). Kinetic studies with a number of peptide substrates indicate that the enzyme preferentially cleaves on the amino side of hydrophobic or basic residues. However, the substrate specificity is more complex since not all basic and hydrophobic residues in a peptide are cleaved. The enzyme exhibits a requirement for a P'2 residue. On the basis of kcat/K(m) values, insulin, growth hormone releasing factor, and beta-endorphin are nearly equivalent substrates for the enzyme; however, growth hormone releasing factor and beta-endorphin exhibit a 40-fold higher kcat, but a 10-fold decreased affinity relative to insulin. A role for insulin-degrading enzyme as both a beta-endorphin-processing and -inactivating enzyme is implicated from these studies.
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PMID:Identification of gamma-endorphin-generating enzyme as insulin-degrading enzyme. 891 18

The presence and regulated expression of peptidase activity is a powerful mechanism with the potential to terminate or alter receptor recognition, cell membrane signal transduction, and physiological responses of immune cells to exogenous opioid peptides. In this study, the expression of an endopeptidase that hydrolyzes beta-endorphin to gamma-endorphin and other peptide products was investigated during in vitro differentiation and maturation of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) -derived, bone marrow-derived macrophages. In freshly isolated intact isolated mouse bone marrow cells the rate of beta-endorphin hydrolysis is undetectable (<0.1 nmol beta-endorphin hydrolyzed/h/10[6] cells). However, total intracellular beta-endorphin hydrolytic activity was increased significantly to 20.0 +/- 1.7 nmol/h/10(6) cells in the mature mouse macrophages derived in vitro by culture with rGM-CSF. rGM-CSF-derived macrophages expressed significantly higher levels of both protein and mRNA for the major beta-endorphin endopeptidase, gamma-endorphin-generating enzyme/insulin-degrading enzyme (gamma-EGE/IDE). Moreover, this enzymatic activity appears to be responsible for cleavage of exogenous beta-endorphin by intact rGM-CSF-derived macrophages or peritoneal macrophages to generate gamma-endorphin and other peptide products.
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PMID:Increased expression of an endopeptidase (gamma-EGE/IDE) hydrolyzing beta-endorphin during differentiation and maturation of bone marrow macrophages. 940 Aug 16

Using purified enzyme preparations, we investigated the actions of angiotensin-converting enzyme, aminopeptidase N, and endopeptidase 24.11 on corticotropin-releasing factor (CRF). The effects of inhibition of these enzymes on CRF action in rat anterior pituitary cultures were also determined. Finally, specific inhibitors were used to evaluate ectopeptidase action on the regional brain metabolism of CRF. K(m) values for CRF were 165, 90, and 42 microM for angiotensin-converting enzyme, aminopeptidase N, and endopeptidase 24.11, respectively. A CRF metabolite profile for each enzyme was determined. In pituitary cultures, inhibition of endopeptidase 24.11 and aminopeptidase N potentiated CRF-stimulated release of adrenocorticotropic hormone (ACTH). In rat pituitary and hypothalamus membrane preparations, specific inhibitor experiments indicated that CRF hydrolysis involved members of the neutral endopeptidase and aminopeptidase enzyme families. In cortex membranes, similar peptidase inhibition was without effect. These data support the hypothesis that ectopeptidases play a major role in CRF metabolism and biological function.
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PMID:Action of three ectopeptidases on corticotropin-releasing factor: metabolism and functional aspects. 1249 37


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