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)

Data from our group and others suggest that pituitary-adrenal activation in major depression reflects a defect at or above the hypothalamus which results in the hypersecretion of corticotropin-releasing hormone (CRH); some have suggested, however, that elevated indices of cortisol secretion and lack of suppressibility to dexamethasone may be a manifestation of a primary defect in glucocorticoid receptor activation. We report here a study of early morning pituitary-adrenal responses to the glucocorticoid antagonist RU 486 in patients with major depression and healthy volunteers. Previous data suggested that the response to RU 486 could represent an index of endogenous CRH secretory activity. RU 486 produced a robust increase in plasma corticotropin (ACTH) and cortisol secretion in both control subjects and depressed patients. In the controls, however, the increase was confined to the last 2 hours of sampling (6 to 8 am), whereas in the depressed patients the increase occurred throughout the sampling period (3 to 8 am). The ACTH response in the depressed patients exceeded that in the controls during most of the sampling period, including a significant (p less than .005) increase between 3 and 4:30 am. These results are compatible with the idea that hypercortisolism in major depression represents an alteration in the overall set point for hypothalamic CRH secretion rather than a primary alteration at the level of the glucocorticoid receptor.
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PMID:Effects of glucocorticoid antagonism with RU 486 on pituitary-adrenal function in patients with major depression: time-dependent enhancement of plasma ACTH secretion. 256 May 55

The three major classes of neurons in the paraventricular nucleus (PVH) provide a rich model for studying hormonal and neural influences on multiple neuropeptides expressed in individual cells. A great deal of previous work has examined this problem at the immunohistochemical level, where hormonal and neural influences on peptide levels have been established. In situ hybridization methods were used here to determine whether these effects are accompanied by measurable changes in neuropeptide mRNA levels. In the first series of experiments, the time-course of corticosterone replacement effects on corticotropin-releasing hormone (CRH) mRNA levels in parvicellular neuroendocrine cells of adrenalectomized animals were determined, and a dose-response curve was established. CRH mRNA hybridization remains maximal with plasma levels of steroid up to about 50 ng/ml, then declines sharply between about 60-130 ng/ml, and is just detectable at higher levels. We confirmed that corticosterone decreases vasopressin mRNA levels in this cell group and showed that levels of preproenkephalin mRNA are also decreased, whereas no significant changes in cholecystokinin, beta-preprotachykinin, and angiotensinogen mRNA levels could be detected. Thus, corticosterone decreases some neuropeptide mRNA levels and has no influence on others in this cell group. Tyrosine hydroxylase mRNA hybridization is also unaffected in this part of the nucleus. In a second group of experiments, the cell-type specificity of corticosterone influences was examined. It was found that while the hormone depresses CRH mRNA levels in parvicellular neurons, it increases such levels in PVH neurons with descending projections, in certain magnocellular neurosecretory neurons, and in a part of the central nucleus of the amygdala, whereas no influence was detected in the rostral lateral hypothalamic area. Furthermore, the stimulatory effects of corticosterone have different threshold levels in different cell groups. Thus, in different types of neurons, corticosterone may increase, decrease, or have no influence on CRH mRNA levels. In contrast, while corticosterone depresses vasopressin mRNA levels in parvicellular CRH neurons, it has no obvious effects on vasopressin mRNA levels in magnocellular or descending neurons; as with CRH, the effects of corticosterone on vasopressin mRNA levels are cell-type specific. In a third series of experiments it was shown that glucocorticoid receptor and mineralocorticoid receptor mRNAs are found in all three cell types in the PVH and that corticosterone tends to produce modest increases in mRNA levels for both receptors. Finally, it was shown that unilateral catecholamine-depleting knife cuts do not change mRNA levels for any of the neuropeptides (or steroid hormone receptors) examined here, although dramatic changes in neuropeptide levels themselves have been shown.4+
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PMID:Differential steroid hormone and neural influences on peptide mRNA levels in CRH cells of the paraventricular nucleus: a hybridization histochemical study in the rat. 256 87

Glucocorticoids rapidly and specifically inhibit transcription of the pro-opiomelanocortin (POMC) gene in the anterior pituitary, thus offering a model for studying negative control of transcription in mammals. We have defined an element within the rat POMC gene 5'-flanking region that is required for glucocorticoid inhibition of POMC gene transcription in POMC-expressing pituitary tumor cells (AtT-20). This element contains an in vitro binding site for purified glucocorticoid receptor. Site-directed mutagenesis revealed that binding of the receptor to this site located at position base pair -63 is essential for glucocorticoid repression of transcription. Although related to the well-defined glucocorticoid response element (GRE) found in glucocorticoid-inducible genes, the DNA sequence of the POMC negative glucocorticoid response element (nGRE) differs significantly from the GRE consensus; this sequence divergence may result in different receptor-DNA interactions and may account at least in part for the opposite transcriptional properties of these elements. Hormone-dependent repression of POMC gene transcription may be due to binding of the receptor over a positive regulatory element of the promoter. Thus, repression may result from mutually exclusive binding of two DNA-binding proteins to overlapping DNA sequences.
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PMID:Glucocorticoid receptor binding to a specific DNA sequence is required for hormone-dependent repression of pro-opiomelanocortin gene transcription. 258 21

Transcription of the pro-opiomelanocortin (POMC) gene is repressed by glucocorticoids in the anterior pituitary gland. We have defined an element within the POMC promoter which is responsible for this regulatory feedback. This element, the "negative glucocorticoid response element" (nGRE), was localized in the proximal region of the POMC promoter and it contains a binding site for the glucocorticoid receptor. Receptor binding to the nGRE was correlated to hormone-dependent repression by using promoter mutagenesis. The nGRE was also shown to contain a binding site for a nuclear protein of the COUP family of transcription factors. Since the binding sites for COUP and the glucocorticoid receptor overlap, glucocorticoid-dependent repression of POMC transcription may result from mutually exclusive binding of these two nuclear transcription factors.
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PMID:Glucocorticoid repression of pro-opiomelanocortin gene transcription. 262 52

In humans, the syndrome of cortisol resistance is characterized by the absence of signs and symptoms of Cushing's syndrome, elevated total and unbound plasma cortisol concentrations, and increases in urinary free cortisol excretion and plasma adrenocorticotropic hormone. In one family, a severely affected member had hypertension and hypokalemic alkalosis associated with increased plasma concentrations of corticosterone and deoxycorticosterone. These patients are resistant to suppression of the pituitary-adrenal axis by dexamethasone. Dexamethasone therapy, however, effectively corrected hypertension and hypokalemic alkalosis in the severely affected patient, without causing signs of glucocorticoid excess. The glucocorticoid receptor from these patients has a low affinity for glucocorticoids and is unstable during thermal activation. Both the molecular weight of the glucocorticoid receptor and the size of the corresponding mRNA are similar to those of normal controls. Transformation of B-lymphocytes with Epstein-Barr virus leads to induction of glucocorticoid receptors. Receptor induction, however, is lower in patient cells than those obtained from normal controls. This decreased induction parallels decreased expression of glucocorticoid receptor mRNA. Thus, in this form of glucocorticoid resistance the glucocorticoid receptor is abnormal and leads to diminished target organ responsiveness. Many New World primates exhibit glucocorticoid "resistance," without apparent pathology. These species have markedly elevated plasma cortisol, both total and unbound concentrations, increased urinary free cortisol excretion, and marked increases in plasma adrenocorticotropic hormone and beta-endorphin. The glucocorticoid receptors of these primates have decreased affinity for glucocorticoids, are thermolabile, and are not induced by Epstein-Barr virus transformation as indicated by specific binding and mRNA expression. Both the molecular weight of the glucocorticoid receptor and the size of the corresponding mRNA are similar to those of normal controls. Despite the high plasma cortisol concentrations in these primates, there is no sodium retention and aldosterone levels are actually increased. The kidney aldosterone receptor cross-reacts poorly with cortisol, explaining the absence of sodium retention. New World primates also have progesterone, estrogen, aldosterone, and vitamin D insensitivity, suggesting a common factor linking steroid hormone receptors.
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PMID:Glucocorticoid resistance in humans and nonhuman primates. 264 36

The gene encoding pro-opiomelanocortin (POMC) is specifically expressed in two different cell types of the pituitary gland. We have defined the regulatory DNA sequences of the POMC gene that are responsible for this cell-specific expression. In addition, we have defined a regulatory element, located in the proximal region of the POMC promoter, that confers glucocorticoid repression in the anterior pituitary. Using DNA-mediated gene transfer into transgenic mice and tissue culture cells, the POMC regulatory sequences required for cell-specific expression and glucocorticoid repression were localized within a 543-bp fragment in the 5'-flanking region of the gene. Multiple regulatory elements that bind nuclear proteins are present within this region. In particular, a sequence that binds the glucocorticoid receptor and behaves as a "negative glucocorticoid response element" (nGRE) also binds nuclear proteins of the COUP (chicken ovalbumin upstream promoter) family of transcription factors. Thus, glucocorticoid repression of POMC transcription may result from the mutually exclusive binding of the glucocorticoid receptor and the COUP transcription factor to the POMC nGRE.
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PMID:Tissue-specific activity of the pro-opiomelanocortin (POMC) gene and repression by glucocorticoids. 269 28

Male rats were exposed to severe 14 day immobilization stress. Body weight, body temperature, food and water intake, behavioral parameters, and serum corticosterone levels were measured during and after the stress period. On the 7th day after cessation of stress the experimental animals together with the control rats were taken to immunocytochemical analysis involving morphometry and microdensitometry of tyrosine hydroxylase (TH), 5-hydroxytryptamine (5-HT), various neuropeptide, and glucocorticoid receptor (GR) immunoreactivities (IRs) in a large number of regions of the central nervous system. In addition, adrenocorticotropic hormone (ACTH) IR was analyzed in the pituitary gland. Seven days following cessation of the chronic stress food intake, total locomotion and forward locomotion had been restored to normal. Serum corticosterone levels appeared to remain increased even 6 days following cessation of the chronic immobilization stress, probably caused by increased release of ACTH. Paraventricular corticotropin releasing hormone (CRF) IR was negatively correlated with the pituitary ACTH IR, indicating that the increase in ACTH release was produced by an increased release of CRF from the hypothalamus. The major immunocytochemical change observed 7 days after cessation of stress was a disappearance of 5-HT IR in the 5-HT cell groups B1, B2, B3, and B7. 5-HT IR in nerve terminals was only affected in the dorsal horn, where 5-HT IR was increased in the substantia gelatinosa. GR IR was found to be significantly increased in monoaminergic cell groups: serotoninergic B7, dopaminergic A12, and noradrenergic A1, A2, and A6. A trend for a reduction of TH IR was observed in nigral DA cells associated with significant reductions in TH IR in striatal DA nerve terminals. Finally, increases in 5-HT and substance P (SP) IR were found in the nerve terminals of the substantia gelatinosa of the cervical spinal cord in the stress group. In the present experimental model evidence has been obtained for a maintained activation of the hypothalamic-pituitary-adrenal axis as evaluated 7 days after cessation of severe chronic immobilization stress. The reduction of 5-HT IR in various 5-HT cell groups indicates a reduction of 5-HT synthesis, which may also be associated with reduced 5-HT release from the nerve terminals, since no depletion was observed in terminal regions and in one case an increase in 5-HT IR was noted (substantia gelatinosa).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Chronic immobilization stress: evidence for decreases of 5-hydroxy-tryptamine immunoreactivity and for increases of glucocorticoid receptor immunoreactivity in various brain regions of the male rat. 276 Jun 6

Serious contradictions exist at present in our understanding of the physiological role of glucocorticoids on the synthesis of the metal-binding protein, metallothionein (MT). In addressing this problem, we have examined in vivo the role of glucocorticoids on liver and serum MT levels in the rat under a spectrum of experimental conditions. The experiments confirm that stress has a major positive effect on hepatic MT levels. It was found that adrenocorticotropic hormone (ACTH) administration has an inhibitory effect on hepatic MT levels in response to restraint stress and that adrenalectomy (ADX) leads to an increase in basal MT levels and in MT levels in response to acute and chronic immobilization stress. Similar results followed treatment with the glucocorticoid receptor blocker, RU 486. The effect of ADX was abolished by corticosterone replacement. The relations found among hepatic MT, serum MT, and glucocorticoid concentrations indicate that in some circumstances glucocorticoids have a permissive role in mobilizing MT from tissues to serum and that in physiological conditions corticosterone has an inhibitory role in the maintenance of hepatic MT levels.
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PMID:Physiological role of glucocorticoids on rat serum and liver metallothionein in basal and stress conditions. 282 14

1. The 41 amino acid peptide human corticotropin releasing hormone (h-CRH) and its ovine analogue o-CRH are regulators of proopiomelanocortin (POMC) derived neuropeptides and neurosteroids of the limbic-hypothalamic-pituitary-adrenocortical (LHPA) axis such as beta-endorphin, corticotropin (ACTH) and corticosteroids modulating concomitantly hormonal and behavioral systems in animal and man, e.g. adaptation to stress. 2. Challenge tests employing h-CRH stimulation with or without different kinds of pretreatment in affective disorders, alcoholism, and panic disorder demonstrate LHPA alterations that are induced by dysregulations in the limbic area. In depression, the enhanced secretory activity of pituitary corticotrophs or altered feedback regulation is compatible with endogenous CRH hypersecretion followed by enhanced production of proopiomelanocortin whose fragments activate synthesis and release of adrenal corticosteroids. These effects are accompanied by development of a functional hyperplasia of the adrenocortex and/or down-regulation of pituitary CRH-receptors and/or reduced negative feed back capacity of limbic glucocorticoid receptor containing neurones particularly in the hippocampus. Similar disturbances are found in hypercortisolemic patients withdrawn from alcohol and are less pronounced in patients with panic disorder. 3. Repetitive h-CRH administration to normal controls induces sleep-EEG and neuroendocrine effects resembling those in depression. 4. Adrenocortical hormones act back on neurotransmitter/receptor sites of brain systems relevant for neuropharmacoloy (e.g. GABA receptor activity in anxiety disorders and affective disorders). 5. The neuroendocrine approach to the LHPA axis is of value to uncover several aspects of pathology underlying various psychiatric diseases.
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PMID:Human corticotropin releasing hormone: clinical studies in patients with affective disorders, alcoholism, panic disorder and in normal controls. 285 97

The antinociceptive effect of parenterally and intracerebroventricularly injected morphine and beta-endorphin in adrenalectomized rats and in adrenalectomized rats treated with adrenal steroids was examined employing the hot-plate method. (1) Adrenalectomy sensitized the rats to an analgesic effect of morphine and beta-endorphin. (2) Replacement therapy (chronic and acute) with corticosterone, dexamethasone or RU 28362 (glucocorticoid receptor agonist) effectively reversed the increase in the sensitivity to the analgesic effect of peripherally injected morphine (5 mg/kg i.p.) induced by adrenalectomy to the level of sham-operated animals. Glucocorticosteroids administered to non-adrenalectomized rats did not change the sensitivity to morphine. (3) Corticosterone had a biphasic, dose-dependent effect; the most significant attenuation of the hypersensitivity to morphine-induced antinociception in adrenalectomized rats was achieved after 0.01 mg and after 10 mg (per kg b.w.). Doses of corticosterone of 0.005 mg/kg and in a range of 0.05-0.30 mg/kg were ineffective. (4) Corticosterone in a dose of 0.01 mg/kg (s.c.) had suppressant effects on the adrenalectomy-induced increase in the sensitivity to antinociception induced by morphine when given prior to morphine (60, 30 and 5 min) as well as after the injection of morphine (before the first and the second testing on the hot-plate, 15 and 5 min, respectively). (5) Intracerebroventricularly (i.c.v.) injected morphine and beta-endorphin also displayed the hypersensitivity to the analgesic effect in adrenalectomized rats which in both cases could be suppressed by 0.01 mg/kg of corticosterone given subcutaneously 5 min prior to administration of the opiate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Corticosteroid effects on morphine-induced antinociception as a function of two types of corticosteroid receptors in brain. 296 13

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