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)

Cyclosporin A (CSA), a potent immunosuppressive drug, has recently been shown to bind with high affinity to the immunophilin, cyclophilin. Calcineurin, the calcium-dependent protein phosphatase, binds the cyclophilin/CSA complex, rendering it inactive and blocking dephosphorylation of phosphoproteins. Very high concentrations of cyclophilin have been reported in the brain with a localization identical to that of calcineurin. We have reported that interleukin-2 (IL-2) releases corticotropin-releasing hormone (CRH) by generation of nitric oxide (NO). Nitric oxide synthase (NOS), the enzyme in nitric oxidergic neurons that converts arginine into citrulline plus NO, is inactive in the phosphorylated state. We hypothesized that cyclosporin might therefore inhibit IL-2-induced acute CRH release by blocking the dephosphorylation of NOS by calcineurin. Consequently, we examined the effect of CSA on the release of CRH from mediobasal hypothalami (MBH) in vitro in 'basal' conditions and in the presence of IL-2, which we had previously shown to stimulate CRH release acutely in this preparation. Incubation of MBH for 30 min with IL-2 (10(-13) M), the concentration that was most effective in previous experiments, evoked a significant release of CRH. CSA at 10(-6) or 10(-8) M did not alter basal release of CRH; however, addition of either concentration completely blocked the IL-2-induced release of CRH. This acute action of CSA within the brain is probably mediated by blockade of the dephosphorylation of NOS by calcineurin.
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PMID:Cyclosporin A inhibits interleukin-2-induced release of corticotropin-releasing hormone. 852 89

Unliganded glucocorticoid receptors (GR) are localized in the cytoplasm and are associated with heat shock protein (hsp)90, hsp70, and a member of the immunophilin family, FK506 binding protein 59 (FKBP59). Several members of the cyclophilin and FKBP families have now been shown to associate with unactivated steroid receptors, however the physiological role these immunophilins play in steroid receptor function is questionable. In the present study we have measured GR binding and nuclear translocation of activated receptor in corticotrope cells following treatment with the immunophilin ligands FK506 and cyclospcrin A (CsA). Extensive GR binding studies in AtT20 cells, a mouse corticotrope tumor cell line failed to demonstrate an effect of FK506 or CsA on either the ability of GR to bind ligand, or on nuclear translocation of the liganded receptor at either a saturating or subsaturating dose of dexamethasone (DEX). Consistent with the binding data, functionally, neither CsA nor FK506 altered the glucocorticoid induced decrease in either proopiomelanocortin (POMC) derived peptide secretion or POMC heteronuclear (hn) RNA expression. Despite the fact these drugs did not modulate the actions of glucocorticoids on corticotrope cells, both FK506 and CsA were potent stimulators of basal beta-endorphin secretion (4-6 fold) from rat anterior pituitary cultures and AtT20 cells. In addition, FK506 and CsA potentiated beta-endorphin secretion induced by corticotropin releasing factor (CRF) and phorbol ester, but had no apparent acute (60 min) effect on POMC hnRNA levels. Unlike the acute actions of these immunosuppressant drugs, chronic (24 h) treatment lead to a decrease in cytoplasmic POMC mRNA with no apparent change in the amount of secreted beta-endorphin. Taken together these data suggest that FK506 and CsA do not alter GR activation or function in corticotrope cells, however, they are potent but short lived stimulators of POMC-derived peptide secretion. The observation that CsA and FK506 stimulate POMC-derived peptide secretion, and potentiate both phorbol ester and CRF induced secretion, suggests that these immunosuppressant drugs are acting upon a common point within these intracellular pathways.
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PMID:Cyclosporin A and FK506 are potent activators of proopiomelanocortin-derived peptide secretion without affecting corticotrope glucocorticoid receptor function. 874 19

Many in vitro studies show estrogen regulation of the hypothalamic pro-opiomelanocortin (POMC) system, including a decrease in hypothalamic POMC mRNA after estradiol treatment. Because such in vivo experiments do not allow one to determine whether peripheral, interacting systems or extra-hypothalamic brain regions are involved in this regulation, we sought to establish whether estrogen acts directly in hypothalamus to decrease POMC mRNA. Using an in vitro approach, we studied effects of estradiol (E2) on POMC/cyclophilin mRNA concentrations (RNAse protection assays) in neuronal cultures derived from day 17 fetal rat hypothalamus. Chemically defined medium was deprived of progesterone for 2 days prior to E2 treatment and for the duration of the study. E2 (10(-13)-10(-9) M) dose-dependently decreased POMC mRNA concentrations during a 2-day treatment. Whereas the lowest dose (10(-13) M) of E2 resulted in a statistically significant 44% decrease in POMC mRNA concentrations relative to control cultures, this inhibitory effect was lost because higher doses (10(-11) and 10(-9) M) did not produce statistically significant decrements (22 and 16%, respectively) in POMC mRNA concentrations. Additional time course studies revealed that this decrease in POMC mRNA can be seen as early as 4 h after E2 (10(-13) M) treatment. We conclude that E2 inhibition of POMC mRNA concentrations in hypothalamic neuronal cultures indicates that this inhibition can occur directly in hypothalamus.
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PMID:Estrogen inhibits hypothalamic pro-opiomelanocortin gene expression in hypothalamic neuronal cultures. 914 11

The testicular regulation of luteinizing hormone (LH) secretion in the adult rhesus monkey is mediated by an indirect action of testosterone to decelerate pulsatile gonadotrophin releasing hormone (GnRH) release. Whether this negative feedback action of testosterone involves regulation of GnRH gene expression is unknown. Therefore, the effect of bilateral orchidectomy on hypothalamic levels of the mRNA encoding this hypophysiotropic factor was examined. The feedback action of testosterone is generally considered to be mediated through non-GnRH cells, and the present experiment provided the opportunity to also examine testicular influences on mRNAs encoding putative hypothalamic factors implicated in the testicular regulation of LH secretion. Adult male rhesus monkeys were orchidectomized (n=5) or sham-orchidectomized (n=5) and killed 6 weeks later, after a castration-induced hypersecretion of LH was established. Separate preoptic and mediobasal hypothalamus containing areas were collected, and levels of GnRH mRNA, as well as those of mRNAs encoding pro-opiomelanocortin (POMC), the gamma-aminobutyric acid (GABA) synthesizing enzymes (glutamic acid decarboxylase 65 and 67; GAD65 and GAD67, respectively), neuropeptide Y, galanin and transforming growth factor (TGF)alpha, were quantified using RNase protection assay. Values were expressed in terms of optical density relative to that of cyclophilin mRNA levels. Bilateral orchidectomy produced a significant increase in GnRH mRNA levels that was restricted to the mediobasal hypothalamus and that was associated with a significant decrease in POMC, GAD65 and GAD67 mRNA levels in this region of the hypothalamus. In contrast, neuropeptide Y, galanin and TGFalpha mRNA levels were not affected by castration. These results indicate that, in the monkey, the deceleration of pulsatile GnRH release that is imposed by the testis, and presumably mediated by testosterone, is associated with a concomitant down regulation of GnRH gene expression in the mediobasal hypothalamus. They also support the notion that this hypothalamic feedback action may be mediated by POMC-and GABA-producing neurones in the mediobasal hypothalamus.
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PMID:Effects of orchidectomy on levels of the mRNAs encoding gonadotropin-releasing hormone and other hypothalamic peptides in the adult male rhesus monkey (Macaca mulatta). 1071 12

In this article real-time quantitative RT-PCR strategies for investigation of mRNA distribution in stress-related corticotropin-releasing hormone (CRH), CRH-binding protein (CRH-BP), and CRH receptors (CRH-R1, CRH-R2) in human gestational tissues are described. The effect of sample and RNA preparation, reverse transcription, and the quantitation strategy were investigated. Both thawing of the sample before homogenization and the RT reaction were identified as critical steps. In contrast, the time-lag from the biopsy until snap-freezing and the homogenization procedure had little effect. The "housekeeping" gene cyclophilin was found to be differently expressed in gestational tissues, compromising its use as internal reference. For relative quantitation of mRNA levels by TaqMan PCR the standard curve method and the comparative C (T) method (DeltaDeltaC (T) or DeltaC (T)' method) were compared. Both calculation strategies delivered similar relative mRNA amounts in identifying the placenta as the main source of CRH and CRH-BP mRNA compared with myometrium and decidua. Consistent results were also obtained for CRH-R1 and CRH-R2 by both methods of calculation. We conclude that the simpler comparative C (T) method is adequate for assessing the mRNA levels of CRH, CRH-BP, and CRH receptors in human gestational tissues.
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PMID:Evaluation of different strategies for real-time RT-PCR expression analysis of corticotropin-releasing hormone and related proteins in human gestational tissues. 1618 79