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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Corticosteroid hormones can enter the brain and bind to two receptor subtypes: the high affinity mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) with approximately 10-fold lower affinity. Under physiological conditions the degree of receptor occupation will range from a predominant MR occupation (at the beginning of the inactive period, under rest) to concurrent activation of MRs and GRs (at the circadian peak and after stress). With in vitro electrophysiological recording techniques we observed that neuronal excitability in the CA1 hippocampal field is under a long-term control of MR- and GR-mediated events. The predominant occupation of MRs is associated with a stable amino acid-carried synaptic transmission; calcium- and potassium-currents are small, as are the responses to biogenic amines. Occupation of GRs in addition to MRs results in a gradual failure of CA1 neurons to respond to repeated stimulation of amino acid-mediated input; ionic conductances and responses to biogenic amines are large. In general, electrical properties recorded when both MRs and GRs are unoccupied (i.e. after adrenalectomy) resemble the responses observed when both receptor types are activated. The corticosterone dependency of electrical properties is thus U-shaped. We conclude that MR occupation may be responsible for the maintenance of information processing in the CA1 field and the stability of the circuit. Additional activation of GRs will initially suppress synaptic activity, but may eventually result in an increased instability and even vulnerability of the neuronal networks.
J Steroid Biochem Mol Biol 1994 Jun
PMID:Steroids and electrical activity in the brain. 804 5

Environmental manipulation alters hippocampal glucocorticoid receptor (GR) expression in neonatal rats, but effects in adults have not been documented. Chronic environmental enrichment (EE) increases nerve-growth factor (NGF) concentrations in the adult rat hippocampus. Here we demonstrate that EE induces GR, but not mineralocorticoid receptor (MR) gene expression in specific hippocampal subfields (CA1 and CA2). This is accompanied by increased expression of mRNA encoding the (NGF-induced) immediate early gene NGFI-A in CA2, whereas expression of NGFI-B mRNA decreased in CA1 and CA2. The nature of any relationship between NGF, the transcription factors and GR remains to be determined, but the results demonstrate that chronic environmental manipulations alter hippocampal GR gene expression in adult rats.
Brain Res Mol Brain Res 1994 Jun
PMID:Glucocorticoid receptor and NGFI-A gene expression are induced in the hippocampus after environmental enrichment in adult rats. 809 75

The enzyme 11 beta-hydroxy steroid dehydrogenase (11 beta-OHSD) was described and its location in various organs noted more than 30 years ago (Mahesh and Ulrich, 1960; Jenkins, 1966). 11 beta-OHSD inactivates circulating glucocorticoids by transforming the hydroxyl group at the 11-carbon to a keto group. This chemical reaction has taken on a greater degree of physiologic and clinical significance in recent years. It has been suggested that 11 beta-OHSD, present in mineralocorticoid target tissues, can act as a 'guardian' over the mineralocorticoid receptor by transforming circulating endogenous glucocorticoids to their respective 'biologically inert' 11-dehydro derivatives (Edwards et al., 1988; Funder et al., 1988). These derivatives do not bind to mineralocorticoid receptors (MR) while both their parent compounds and mineralocorticoids bind to cloned MR with equal affinity (Arriza et al., 1987). 11 beta-OHSD has generated a growing sense of scientific excitement since this enzyme may represent one of a family of metabolic pathways or mechanisms which can regulate steroid induced renal reabsorption of sodium. Such 'protective' enzymatic pathways, present in the kidney and elsewhere, may not only control the access of glucocorticoids to MR, but control the access of glucocorticoids to glucocorticoid receptors (GR) (Teelucksingh et al., 1990; Monder, 1990) as well as access of mineralocorticoids to their own receptors. This review will focus on this concept of a family of protective enzymatic pathways and the possible physiological implications.
Mol Cell Endocrinol 1993 Nov
PMID:Interactions between glucocorticoids and mineralocorticoids in the regulation of renal electrolyte transport. 814 89

The human progesterone receptor (hPR) exists as two distinct molecular forms in most cells, hPR-A and -B. These receptor isoforms display distinct biological functions and demonstrate a cell and promoter specific ability to regulate gene transcription. In cellular contexts where hPR-A is transcriptionally inactive it can function as a ligand dependent inhibitor of mineralocorticoid receptor (MR) transcriptional activity. Inhibition occurs by a non-competitive mechanism as direct binding to MR is not required. Interestingly, PR agonists differ in their ability to facilitate the inhibitory function of hPR-A, suggesting that a specific receptor conformation may be preferred for this activity. Those compounds derived from 19-nor-testosterone are the most effective. The antiprogestins RU486, ZK98299 and ZK112993 are effective MR antagonists in the presence of coexpressed hPR-A. The mechanism of hPR-A mediated inhibition of MR transcriptional activity is unknown. We propose that inhibition results from a competition of hPR-A with MR for a common transcription factor and that the association of hPR-A with this factor is not transcriptionally productive.
J Steroid Biochem Mol Biol 1994 Apr
PMID:The human progesterone receptor A-form functions as a transcriptional modulator of mineralocorticoid receptor transcriptional activity. 818 Jan 3

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) by converting active glucocorticoid to an inactive metabolite confers specificity upon the mineralocorticoid receptor (MR) and regulates ligand access to the glucocorticoid receptor (GR). Factors which influence 11 beta-HSD activity seem likely to be of considerable importance in the modulation of both mineralocorticoid and glucocorticoid hormone action. The administration of tri-iodothyronine (T3) to rats has previously been shown to reduce 11 beta-HSD activity in liver but not in kidney. We have studied the effect of T3 on 11 beta-HSD gene expression in vivo in rat liver, kidney, distal colon and pituitary. In addition the effects of T3 on 11 beta-HSD gene expression in vitro in the rat pituitary GH3 cell line have been studied. T3 administration to normal adult rats (40 micrograms/day, s.c. for 1, 3 and 7 days) resulted in a marked decline in liver and pituitary 11 beta-HSD mRNA levels and activity following 3 and 7 days of treatment. These reduced levels were maintained for 3 days following withdrawal of T3 treatment, but returned to control levels after 7 days. In contrast 11 beta-HSD mRNA and activity in kidney and distal colon were unaffected by T3 treatment at each time point studied. In vitro, levels of 11 beta-HSD mRNA and activity in GH3 cells were unchanged following 8, 24 and 72 h treatment with T3 (10(-8) to 10(-6) M). T3 bio-activity was confirmed by a marked dose-dependent decline in the expression of the T3 and glucocorticoid responsive gene, prolactin. T3 inhibits 11 beta-HSD gene expression in both liver and pituitary at a pre-translational level. This effect is absent in the predominantly mineralocorticoid target tissues, kidney and distal colon, i.e. it is tissue specific and as such is consistent with the existence of multiple differentially regulated isoforms of 11 beta-HSD. The time course of the T3 effect in liver and pituitary in vivo and the lack of any effect in vitro suggests that this action is indirect, and not as a result of interaction between the T3 receptor and the putative thyroid hormone response element on the rat 11 beta-HSD gene.
J Steroid Biochem Mol Biol 1993 Nov
PMID:Tissue specific effects of thyroid hormone on 11 beta-hydroxysteroid dehydrogenase gene expression. 824 Sep 75

Using a synthetic peptide that corresponds to a unique region of the N-terminal domain of the human mineralocorticoid receptor (MR), amino acids 87-96, we have generated a polyclonal antibody, human (h) MRsN. This sequence shares no homology with the corresponding sequences of the glucocorticoid receptor or other steroid/thyroid hormone receptor superfamily members. Antibody hMRsN cross-reacts with MR from human, rat, and mouse cells and recognizes denatured MR from either crude preparations or partially purified rat kidney cytosol, rat colon, or recombinant hMR overexpressed in baculovirus-infected Sf9 cells. Immunoprecipitation of the native MR from either partially purified or crude preparations of rat kidney cytosol with hMRsN, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver stain, demonstrated a major protein band with a mol wt of 116 kilodaltons. In addition, using confocal laser scanning microscopy and digital image analysis, the immunocytochemical localization of the recombinant hMR over-expressed in Sf9 cells 24 h post-transfection was determined. In the absence of ligand, the MR was detected solely in the cytoplasm, after a 30-min exposure to 100 nM aldosterone the MR was perinuclear, and after 60 min, the MR was predominantly nuclear. To ascertain that this phenomenon was not unique to insect cells, aldosterone induced MR nuclear translocation in mouse macrophage cells was also demonstrated immunocytochemically, clearly indicating a role for nuclear translocation in MR function.
Mol Endocrinol 1993 Sep
PMID:Demonstration of nuclear translocation of the mineralocorticoid receptor (MR) using an anti-MR antibody and confocal laser scanning microscopy. 824 24

1. In the brain, glucocorticoids bind to both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). These receptors show clearly distinct developmental patterns in the infant rat. 2. Low levels of GRs are present around the time of birth throughout the brain. Concentrations rise slowly, and do not achieve adult levels until the third week of life, approximately. GR affinity for corticosterone is higher perinatally than at later ages. Receptor microdistribution changes dramatically during ontogeny. In particular, certain regions, such as the suprachiasmatic nucleus of the hypothalamus, express high levels of receptor only during the first week of life. GRs may show impaired capacity to undergo transformation and/or nuclear translocation during the second postnatal week. Environmental manipulations during early ontogeny (e.g., early handling) may have permanent effects on GR capacity. 3. MRs are present at very low concentrations in the first days of life. Binding capacity rises rapidly thereafter and resembles that found in the adult by the end of 1 week. Neither binding affinity in vitro nor overall distribution changes with age. As in the adult, low doses of corticosterone, in vivo, bind mainly to the MRs. Levels of corticosterone are low and relatively unperturbable in the intact infant rat. It is likely, therefore, that most of the physiological actions of this hormone during this period are mediated by the MR.
Cell Mol Neurobiol 1993 Aug
PMID:Ontogeny of corticosteroid receptors in the brain. 825 5

Two distinct isoforms of the human progesterone receptor (hPR-A and hPR-B) have been identified previously. They differ only in that hPR-B contains an additional 164 amino acids at the amino terminus. Among various species these two forms arise as a result of either alternate initiation of translation from the same mRNA or by transcription from alternate promoters within the same gene. In order to understand the reason for their existence, we studied the transcriptional capacity of these individual receptors and observed that their activity was influenced strongly by cell and promoter context. More surprising was the observation that in promoter and cell contexts where hPR-A was inactive, it acted as a potent trans-dominant repressor of hPR-B-mediated transcription. This event occurred at substoichiometric concentrations of hPR-A and was hormone dependent. Human PR-A was not a general repressor of ligand-mediated transcription, as it had no effect on vitamin D receptor function. Interestingly, hPR-A but not hPR-B was capable of a similar inhibition of glucocorticoid, androgen, and mineralocorticoid receptor-mediated gene transcription. This suggests a specific role for the hPR-A isoform in this regulatory process. The trans-dominant effects of hPR-A were induced also by the antiprogestins ZK112993 and ZK98299 and a DNA binding defective hPR-A mutant, suggesting that the inhibitory function of hPR-A does not require DNA binding. The dual role of hPR-A as an activator or repressor of transcription defines a potential mechanism by which cells can generate dissimilar responses to a single hormone and provides a molecular explanation for the existence of two distinct forms of the hPR.
Mol Endocrinol 1993 Oct
PMID:Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. 826 57

In arterial hypertension associated with primary or secondary hyperaldosteronism myocardial fibrosis is an important determinant of pathologic hypertrophy. To further examine the relationship between elevations in plasma aldosterone (ALDO) and myocardial fibrosis, we analysed perivascular collagen area (PVCA) and interstitial collagen volume fraction (CVF) by videodensitometry and hydroxyproline concentration (HPro) by high-performance liquid chromatography. We examined both the left (LV) and right (RV) ventricles in the following rats models of primary or secondary hyperaldosteronism of eight weeks duration: unilateral renal ischemia (RHT); continuous ALDO administration via osmotic minipumps (0.75 microgram/h s.c.) and enhanced dietary sodium following uninephrectomy (AL); in RHT and AL after pre- and continuous treatment with either 20 (S) or 200 (SS) mg/kg/day s.c. of the aldosterone receptor antagonist, spironolactone; in AL after pre- and continuous treatment with 50 mg/kg/day oral captopril (AL + CAP); as well as in age and sex matched controls (C). Systolic arterial pressure was comparably elevated in RHT and AL (202 +/- 12 and 193 +/- 7 mmHg, respectively; P < 0.0005 vs C); it remained elevated with low dose spironolactone in either model of arterial hypertension, but was normalized with high dose spironolactone or captopril in AL. Left ventricular hypertrophy (LVH), expressed as significantly elevated LV/RV weight or LV/BW ratios, was present in all experimental groups, excluding AL + SS and AL + CAP, when compared with C (P < 0.005). In each ventricle, CVF and PVCA were increased (P < 0.005) in either model of hypertension and in AL + CAP, but were no different from C in all groups receiving either dose of spironolactone. Similar findings were observed for HPro. Thus, myocardial fibrosis was comparable in primary or secondary hyperaldosteronism, wherein elevations in plasma aldosterone, relative to increased sodium intake, are associated with arterial hypertension. The competitive ALDO receptor antagonist, spironolactone, was able to prevent fibrosis in either model irrespective of the development of LVH and the presence of hypertension. Captopril prevented hypertension and LVH, but not unexpectedly it did not prevent myocardial fibrosis in primary hyperaldosteronism. These findings provide further evidence that in these rat models increased plasma ALDO, relative to dietary sodium, plays a major role in the adverse accumulation of collagen that appears in the myocardium.
J Mol Cell Cardiol 1993 May
PMID:Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. 837 16

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) interconverts cortisol and cortisone. Congenital deficiency of the renal isoform of the enzyme results in hypertension, hypokalemia and suppression of the renin-angiotensin-aldosterone system--the apparent mineralocorticoid excess syndrome (AME). In these patients cortisol acts as a potent mineralocorticoid. Suppression of plasma cortisol with dexamethasone results in natriuresis, potassium retention and reduction in blood pressure. Ingestion of excess liquorice or taking carbenoxolone produces an acquired form of AME. The active component of liquorice is glycyrrhetinic acid (GE) and carbenoxolone is the hemisuccinate derivative. Both GE and carbenoxolone are potent inhibitors of 11 beta-OHSD. In vitro studies have shown that 11 beta-OHSD is present in aldosterone-selective tissues and acts as an autocrine mechanism which prevents cortisol from gaining access to the non-specific mineralocorticoid receptor (MR). Congenital or acquired absence of this enzyme allows cortisol to bind to MR resulting in AME. 11 beta-OHSD also appears to be important in controlling cortisol access to glucocorticoid receptors. Variable placental 11 beta-OHSD may alter foetal exposure to maternal cortisol and affect growth as indicated by the correlation between foetal weight and placental 11 beta-OHSD. Thus the tissue-specific distribution, ontogeny and modulation of this enzyme allows it to dictate glucocorticoid effects in addition to its key role in ensuring the specificity of the MR.
J Steroid Biochem Mol Biol 1993 Apr
PMID:Congenital and acquired syndromes of apparent mineralocorticoid excess. 838 30


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