Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 presence of glucocorticoid receptor (GR) in the anterior lobe of the pituitary gland has previously been demonstrated, but the exact cell types expressing GR have not yet been characterized. In this study, we demonstrate the colocalization of GR and pituitary hormones in the rat pituitary gland by using an immunocytochemical double-labelling method. The majority of anterior lobe corticotropin-immunoreactive and growth hormone-immunoreactive cells contained GR-like immunoreactivity. Cells of the intermediate lobe showed intensive ACTH-like immunoreactivity but did not express GR. The glycoprotein hormones thyroid-stimulating hormone, follicle-stimulating hormone and luteinizing hormone were colocalized with GR to a lesser degree; approximately one-half of the cells exhibited immunoreactivity to these hormones contained GR. By contrast, only a minority of the prolactin-immunoreactive cells expressed GR. Our results suggest that glucocorticoids may differentially regulate the secretion and/or synthesis of these pituitary hormones by directly affecting the hormone-producing cells of the anterior pituitary.
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PMID:Glucocorticoid receptor colocalization with pituitary hormones in the rat pituitary gland. 831 36

Although corticotropin releasing factor (CRF) and glucocorticoid hormones (GC) act directly at the level on the anterior pituitary corticotrope cell to stimulate (CRF) or inhibit (GC) pro-opiomelanocortin (POMC) expression, the actions of GC on POMC have been shown to be impaired if corticotrope cells are coincubated or preincubated with CRF. In the present study we have measured secreted beta-endorphin (beta EP) and changes in the level of nuclear POMC hnRNA as an indirect measure of gene transcription to characterize the molecular mechanisms involved in the CRF-mediated inhibition of glucocorticoid action. In primary cultures of rat anterior pituitary cells either co-treated or pretreated with CRF, acute dexamethasone (DEX)-mediated inhibition of POMC hnRNA levels was impaired. In contrast, the ability of CRF to block glucocorticoid action was abolished if the cells were pretreated with the protein synthesis inhibitor puromycin. Since previous studies have demonstrated that components of the AP1 transcription factor can modulate glucocorticoid receptor activity in other systems, we examined the regulation of the proto-oncogenes c-fos and c-jun in response to CRF. Treatment of the corticotrope cell line (AtT-20) with CRF rapidly activated c-fos mRNA to levels 11-12-fold above control by 30 and 60 min, with no apparent elevation of c-jun mRNA levels. Pretreatment of AtT-20 cells with antisense c-fos oligonucleotides prevented CRF from blocking glucocorticoid inhibition of POMC hnRNA levels and beta EP release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Corticotrope responsiveness to glucocorticoids is modulated via rapid CRF-mediated induction of the proto-oncogene c-fos. 837 73

Apparent mineralocorticoid excess (AME) is a rare form of low renin hypertension caused by deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), the enzyme responsible for conversion of cortisol to the bio-inactive metabolite, cortisone. This results in prolonged cortisol half-life, activation of type I (mineralocorticoid) receptors by cortisol, sodium and fluid retention, and consequent childhood-onset hypertension. The cortisol secretion rate is low, perhaps due to cortisol's binding to type II (glucocorticoid) receptors and suppressing corticotropin secretion. Patients with AME thus lack stigmata of Cushing's syndrome. To evaluate any potential contribution of the type II (glucocorticoid) receptor to the development of hypertension in AME patients, we administered RU486, a steroid analogue that acts as a pure type II receptor blocker. Selective glucocorticoid receptor blockade did not decrease blood pressure in our patient; instead, a significant increase in average blood pressure was observed (125.1 +/- 1.7 pre-RU486 v 144.7 +/- 1.2 during RU486 treatment, P = .0001). We conclude that the type II receptor does not contribute to the development of hypertension in patients with AME.
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PMID:Investigation of the mechanism of hypertension in apparent mineralocorticoid excess. 839 54

The effect of intracerebroventricular (icv) infused corticotropin-releasing hormone (CRH), 300 ng, infused at a rate of 16.67 ng/min during 18 min and its relation to the functioning of brain corticoid receptors was investigated in freely moving rats in their home cages. Behavior was sampled before, during, and after the CRH infusion. Cardiovascular measurements were made via a chronically implanted catheter in the descending aorta. Blood samples were withdrawn to determine adrenal hormone concentration. Central administration of the brain mineralocorticoid-like receptor (MR) antagonist (RU 28318, 100 ng) and the glucocorticoid receptor (GR) antagonist (RU 38486, 100 ng) 60 min before CRH infusion served to manipulate adrenal steroid states in the brain. CRH infusion caused behavioral activation which was associated with an increase in heart rate (HR) and mean arterial blood pressure (MAP). Increased plasma corticosterone and norepinephrine levels were observed, while a minor elevation of epinephrine (E) levels also occurred. Both corticoid receptor antagonists failed to affect the CRH-induced behavioral activation. Administration of the GR antagonist significantly enhanced the magnitude of the CRH-induced increase in E, whereas the effect of the MR antagonist just failed to reach significance. These findings suggest the involvement of central corticoid receptors in sympathoadrenomedullary feedback mechanisms. The MR antagonist elevated baseline MAP probably thereby suppressing the magnitude of the CRH response. The increase in HR was diminished by both antagonists shortly after CRH infusion. Together, the data suggest involvement of brain corticosteroid receptor-mediated processes in neuroendocrine and cardiovascular effects of CRH.
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PMID:Central actions of corticotropin-releasing hormone (CRH) on behavioral, neuroendocrine, and cardiovascular regulation: brain corticoid receptor involvement. 839 79

In the studies reported here we have examined the role of the medial prefrontal cortex (MpFC) in regulating hypothalamic-pituitary-adrenal (HPA) activity under basal and stressful conditions. In preliminary studies we characterized corticosteroid receptor binding in the rat MpFC. The results revealed high-affinity (Kd approximately 1 nM) binding with a moderate capacity (42.9 +/- 3 fmol/mg) for 3H-aldosterone (with a 50-fold excess of cold RU28362; mineralocorticoid receptor) and high-affinity (Kd approximately 0.5-1.0 nM) binding with higher capacity (183.2 +/- 22 fmol/mg) for 3H-RU 28362 (glucocorticoid receptor). Lesions of the MpFC (cingulate gyrus) significantly increased plasma levels of both adrenocorticotropin (ACTH) and corticosterone (CORT) in response to a 20 min restraint stress. The same lesions had no effect on hormone levels following a 2.5 min exposure to ether. Implants of crystalline CORT into the same region of the MpFC produced a significant decrease in plasma levels of both ACTH and CORT with restraint stress, but again, there was no effect with ether stress. Neither MpFC lesions nor CORT implants had any consistent effect on A.M. or P.M. levels of plasma ACTH or CORT. Manipulations of MpFC function were not associated with changes in the clearance rate for CORT or in corticosteroid receptor densities in the pituitary, hypothalamus, hippocampus, or amygdala. Taken together, these findings suggest that MpFC is a target site for the negative-feedback effects of glucocorticoids on stress-induced HPA activity, and that this effect is dependent upon the nature of the stress.
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PMID:The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. 839 70

In recent years the techniques of molecular and cellular biology have made it possible to begin to dissect the origins and behaviour of the ACTH-secreting tumour cell. It is becoming apparent that these tumours represent undifferentiated neuroendocrine cells, and it may be that their peptide-secreting properties may have no more sinister oncological significance. However, an autocrine role for beta-endorphin may confer a selective growth advantage on the POMC-expressing cell. It is still not clear why glucocorticoids fail to inhibit the POMC gene in these extra-pituitary tumours despite the presence of glucocorticoid receptors. This may not be resolved until the mechanism for inhibition of POMC by glucocorticoids in the normal pituitary is understood, although it is tempting to speculate that a mutation in the glucocorticoid receptor or a tissue specific interaction is responsible for the resistance of POMC observed in the ectopic ACTH syndrome. In studying the peptides secreted by the extra-pituitary tumours responsible for the ectopic ACTH syndrome it would appear that direct measurement of ACTH precursors and comparison with the circulating concentrations of ACTH can give valuable information on the percentage of tumours which do not effectively process the ACTH precursors. However, far more data have to be collected on patients with occult tumours in order to identify whether this type of processing is tissue specific. Nevertheless, these studies provide useful insights into the mechanisms of intracellular signalling and regulation in such tumours which may identify unique pharmacological tools to inhibit ACTH secretion or more importantly tumour growth.
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PMID:The cellular and molecular basis of the ectopic ACTH syndrome. 839 10

Previous studies defined a DNA element necessary for glucocorticoid repression of the pro-opiomelanocortin (POMC) gene. The glucocorticoid receptor (GR) binds this negative glucocorticoid response element (nGRE) with an in vitro affinity similar to that of GR for positive GREs. However, whereas GR binds GREs as homodimers, a novel GR complex which forms with nGRE appears to contain three GR molecules. Biochemical characterization of this complex as well as equilibrium binding studies suggest that it is formed by sequential binding of a GR homodimer followed by binding of a GR monomer on the opposite side of the double helix. The DNA-binding domain (DBD) of GR is sufficient for differential binding of GRE and nGRE, as bacterially-expressed DBD formed unique nGRE complexes that contain three GR polypeptides. Thus, the POMC nGRE provides the first example of an interaction between GR and DNA in which GR binds otherwise than as a homodimer. Despite its high affinity for GR, the nGRE differs significantly from GREs in that it does not activate transcription in any context. As the nGRE appears insufficient on its own to confer hormone responsiveness, other POMC promoter elements are likely to be required to mediate glucocorticoid repression.
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PMID:Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene. 842 74

The type I glucocorticoid receptor antagonist spironolactone was administered to healthy volunteers to determine the effect of type I receptor blockade on adrenocorticotropic hormone (ACTH) and cortisol secretion in humans. On separate days and in a double-blind, randomized fashion, placebo and each of four increasing doses of spironolactone were administered orally to subjects. Doses were selected to be within the clinically used range and, following drug administration, baseline and ovine-corticotropin releasing hormone (oCRH)-stimulated ACTH and cortisol plasma levels were measured. In contrast to the clear effects of type II glucocorticoid receptor blockade on human pituitary adrenal function, no relationship between spironolactone dose or plasma levels and either basal or oCRH-stimulated pituitary-adrenal function was noted at doses comparable to those which induce type I receptor blockade and cardiovascular therapeutic effects in the kidney. These data suggest that, at physiologically relevant doses, type I glucocorticoid receptor blockade does not affect HPA axis function.
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PMID:Type I glucocorticoid receptor blockade does not affect baseline or ovine corticotropin-releasing-hormone-stimulated adrenocorticotropic hormone and cortisol secretion. 852 92

Impaired cognitive function and enhanced activity of the hypothalamic-pituitary-adrenocortical system are among the cardinal symptoms of major depression in humans that resolve after successful antidepressant treatment. We used a transgenic mouse model expressing antisense RNA complementary to that of glucocorticoid receptor (GR) mRNA to test the hypothesis that reduced GR function can cause these clinical disturbances. The transgenic mice show profound behavioural changes in a number of animal tests that are indicative of cognitive impairment. These mice also have elevated plasma corticotropin concentrations in response to stress. After long-term treatment with moclobemide, a reversible inhibitor of monoamine oxidase type A that acts clinically as an antidepressant, both the behavioural deficits and the hormonal alterations disappeared. These observations suggest that a transgenic mouse with GR dysfunction may be a useful model for investigation of drug effects on the cognitive and neuroendocrine aspects of depression.
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PMID:Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function. 874 20

In gonadectomized (GDX) animals replaced with subcutaneous steroid implants supplying physiological levels of testosterone (T; 1-10 ng/ml), the magnitude of adrenocorticotropic hormone (ACTH) and corticosterone (B) responses to restraint was negatively correlated with the level of T replacement, reflecting the inhibitory influence of T on hypothalamic-pituitary-adrenal (HPA) responses to stress. Although T had no effect on resting-state levels of corticotropin-releasing hormone (CRH) in the median eminence, arginine vasopressin (AVP) levels were significantly lower in GDX animals replaced with higher T levels, and the magnitude of the ACTH response to restraint was strongly correlated with median eminence levels of AVP. High physiological levels of T increased glucocorticoid receptor binding in the medial preoptic area (MPOA), with no effect on mineralocorticoid receptor binding or on glucocorticoid receptor binding in other regions. Crystalline T or B implants in the MPOA significantly reduced plasma ACTH and B responses to 10 min of restraint stress compared with cholesterol-implanted controls. Moreover, B or T MPOA implants also decreased resting-state levels of AVP but not CRH in the median eminence, and these effects were correlated with ACTH responses to restraint. Finally, lesioning the MPOA blocked the inhibitory effects of high peripheral T levels on ACTH and B responses to restraint. Thus, variations in the magnitude of HPA responses to stress among males are explained in part by individual differences in circulating T levels, and the MPOA is a critical site for this effect via the inhibition of hypophysial AVP.
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PMID:The inhibitory effect of testosterone on hypothalamic-pituitary-adrenal responses to stress is mediated by the medial preoptic area. 877 55


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