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Query: UNIPROT:P06889 (Mol)
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Rat brain expresses two types of corticosteroid-binding proteins. The type I receptor binds corticosterone with high affinity and is structurally related to the kidney mineralocorticoid receptor (MR), while the type II or classical glucocorticoid receptor binds corticosterone with lower affinity and displays an in vivo preference for dexamethasone. Here we describe the isolation and characterization of a cDNA coding for the MR, from a rat hippocampus cDNA library, by low stringency hybridization to radiolabeled human glucocorticoid receptor cDNA. The nucleotide and deduced amino acid sequence for rat hippocampal MR displays extensive homology to a MR cDNA isolated from human kidney, suggesting that they are orthologous genes. Southern analysis suggests that there is only one gene for the MR, and in vitro expression of the receptor generates a high affinity corticosterone-binding protein. These data provide evidence to support the contention that a single gene gives rise to the MR in renal tissues and type I receptors in the brain.
Mol Endocrinol 1989 Nov
PMID:Molecular cloning of a mineralocorticoid (type I) receptor complementary DNA from rat hippocampus. 255 5

The molecular structures of 19-nor-11-deoxycorticosterone (III) and 21-hydroxypregna-4,11-diene-3,20-dione (IV) were determined by X-ray crystallographic analysis and the factors affecting the binding affinities for the mineralocorticoid receptor were examined with six aldosterone derivatives (I-VI) containing these two compounds. The most important factor was found to be the steric one; affinity increased with increasing flatness of the structure. The electronic factor may be a minor influence although a good relationship was found between the affinity and the 13C-NMR chemical shift of the C(5) atom. The factor playing no role in the binding is the hydrophobic one.
Mol Pharmacol 1986 Dec
PMID:Relationships of the molecular structure of aldosterone derivatives with their binding affinity for mineralocorticoid receptor. 302 11

The sequence of a splice variant of the rat mineralocorticoid receptor (MR) gene is presented. A cDNA clone corresponding to rat MR was isolated from a rat brain cDNA library. Sequence analysis of the region corresponding to the DNA binding domain revealed the presence of a 12 base pair (bp) insertion. Analysis of mRNA from several rat tissues suggests that the variant is less abundant than the wild type in most tissues. The insertion variant is also a product of the human MR gene, the identical splice variant was also observed in human white blood cell mRNA. Unlike other splice variants reported for the MR, this variant alters the encoded protein by the addition of four amino acid residues in the DNA binding domain. The altered protein may influence the affinity of the MR for mineralocorticoid or glucocorticoid response elements.
J Steroid Biochem Mol Biol 1995 Nov
PMID:Identification of a splice variant of the rat and human mineralocorticoid receptor genes. 749 94

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD), responsible for the interconversion of hormonally active cortisol to inactive cortisone, dictates specificity for the mineralocorticoid receptor (MR) in the distal nephron and colon. Two isoforms of human 11 beta-HSD have been cloned, an NADP(H)-dependent (type 1) dehydrogenase/oxo-reductase enzyme, and a high-affinity NAD-dependent (type 2) unidirectional dehydrogenase. Using the reverse-transcriptase polymerase chain reaction (RT-PCR) amplification of RNA extracted from human adult tissues, type 1 11 beta-HSD mRNA was found in decidua, placenta, liver, lung, spleen, kidney medulla, cerebellum and pituitary, but was absent in kidney cortex, sigmoid and rectal colon, salivary gland and thyroid. In contrast, type 2 11 beta-HSD mRNA was found only in placenta and in the classical mineralocorticoid target tissues, kidney cortex, kidney medulla, sigmoid and rectal colon, salivary gland, and colonic epithelial cell lines (AAC1 and RGC28). In situ hybridization studies of renal cortex, cortico-medullary junction and medulla using a 35S-labeled antisense cRNA probe for type 2 human 11 beta-HSD, revealed specific localization of type 2 11 beta-HSD mRNA expression exclusively to renal cortical and medullary collecting ducts. Type 1 and type 2 isoforms of human 11 beta-HSD are expressed in a distinct tissue-specific fashion, in keeping with the proposed differences in their physiological roles. Type 2 11 beta-HSD is found predominantly in mineralocorticoid target tissues where it serves to protect the MR in an autocrine fashion.
Mol Cell Endocrinol 1995 Apr 28
PMID:Detection of human 11 beta-hydroxysteroid dehydrogenase isoforms using reverse-transcriptase-polymerase chain reaction and localization of the type 2 isoform to renal collecting ducts. 754 19

Hippocampal CA1 neurons express both mineralocorticoid and glucocorticoid receptors. Due to the difference in affinity of the two receptor types for corticosterone and variations in endogenous steroid levels, occupation of the receptors will range between a situation of predominant mineralocorticoid receptor activation and conditions where both receptor types are occupied. It was observed that local signal transduction is regulated by activation of the corticosteroid receptors. Particularly, transmission mediated by biogenic amines appears to be sensitive to steroid control. The data indicate that cholinergic and serotonergic responses are small with predominant mineralocorticoid receptor activation, while additional glucocorticoid receptor activation results in large responses; the reverse has been found for noradrenalin. The steroid-dependent control over transmission by biogenic amines will influence local excitability and therefore functional processes in which the hippocampal system is involved.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Long-term control of neuronal excitability by corticosteroid hormones. 762 73

We investigated the mechanisms by which corticosteroids regulate the expression of the mineralocorticoid receptor (MR) in neurones. Aldosterone and dexamethasone produced a dose-dependent increase of MR and mRNA levels in cultured primary hippocampal neurones. Transient transfection of neuroblastoma cells showed that corticosteroids directly activate the rat MR promoter, indicating that the steroid-induced increase in the MR mRNA concentration is at least partially transcriptional. Progressive 5' deletions of the MR promoter sequence revealed that the promoter induction cannot be assigned to a single element. An oligonucleotide comprising a consensus half-glucocorticoid responsive element located at -319 bp in the MR promoter stimulated the corticosteroid-induced activation of the heterologous promoter. Cloning three of these enhancers in tandem greatly potentiated the responses to glucocorticoids and mineralocorticoids, suggesting that although this element is a weak enhancer it can, in combination with other enhancer elements, induce MR gene expression by both types of corticosteroid receptors.
J Mol Endocrinol 1995 Jun
PMID:Transcriptional induction of rat mineralocorticoid receptor gene in neurones by corticosteroids. 766 20

Pseudohypoaldosteronism is a syndrome characterized by salt wasting and a failure to thrive due to the resistance towards the action of aldosterone. Aldosterone levels and plasma renin activity are extremely elevated and aldosterone binding sites in peripheral mononuclear leukocytes have regularly shown to be reduced or absent. Sporadic as well as familial cases have been identified and an autosomal dominant as well as an autosomal recessive mode of inheritance has been described. A defect in the aldosterone receptor has been postulated, however, molecular genetic analysis in selected patients has not revealed a mutation in the sequence of the coding region of the cDNA of the mineralocorticoid receptor gene. In the present study we have used a fluorescence-labeled antibody to detect possible receptor expression in monocytes from patients with various clinical forms of pseudohypoaldosteronism. Patients with the sporadic as well as with the autosomal dominant form were clearly immunopositive despite being negative in terms of aldosterone receptor binding. In contrast in two patients with the autosomal recessive form there was no detectable receptor protein, consistent with the results obtained in the aldosterone binding studies. These results suggest that the pathogenesis of pseudohypoaldosteronism is heterogeneous not only regarding the mode of inheritance but also in terms of receptor binding. Thus, in a subgroup of patients the inability of the receptor to bind ligand may be due to a defect involving other, probably cellular factors rather than a deficiency or a defect in the mineralocorticoid receptor system itself.
J Steroid Biochem Mol Biol 1994 Dec
PMID:Immunofluorescence of mineralocorticoid receptors in peripheral lymphocytes: presence of receptor-like activity in patients with the autosomal dominant form of pseudohypoaldosteronism, and its absence in the recessive form. 782 88

Postnatal handling alters hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Handling also increases hippocampal glucocorticoid receptor density, and this effect appears to form, in part at least, the basis for the effect of handling on HPA responsiveness to stress. In the present study we have used in situ hybridization techniques to examine the effect of postnatal handling on the expression of glucocorticoid and mineralocorticoid receptor mRNAs in various cell fields of the dorsal hippocampus in adult rats. Grain counting analysis over individual cells showed that postnatal handling significantly increased (40-50%) glucocorticoid receptor mRNA in all hippocampal cell fields. In contrast, handling had no effect on mineralocorticoid receptor mRNA expression. These findings are consistent with the results of receptor binding studies showing that handling increases hippocampal glucocorticoid receptor, but not mineralocorticoid receptor density. Thus, the increase in glucocorticoid receptor binding in handled animals is likely associated with altered rates of receptor biosynthesis. Moreover, the handling effect is quite specific, altering glucocorticoid receptor, but not mineralocorticoid receptor mRNA expression. The mechanism(s) whereby glucocorticoid receptor gene expression is permanently increased by postnatal handling remains to be determined.
Brain Res Mol Brain Res 1994 Oct
PMID:Postnatal handling alters glucocorticoid, but not mineralocorticoid messenger RNA expression in the hippocampus of adult rats. 785 53

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) is thought to protect the non-selective mineralocorticoid receptor from occupation by glucocorticoids, and to modulate access of glucocorticoids to glucocorticoid receptors resulting in protection of the fetus and gonads. A ubiquitous low affinity NADP+ dependent enzyme (11 beta HSD1) and a tissue specific, high affinity NAD+ dependent form (11 beta HSD2) of 11 beta HSD exist. We now report the isolation of a cDNA coding for human 11 beta HSD2. The new isoform is NAD+ dependent, exclusively dehydrogenase in directionality, inhibited by glycyrrhetinic acid and metabolizes the synthetic glucocorticoid dexamethasone; it displays Km values for corticosterone and cortisol of 5.1 nM and 47 nM, respectively. Sequence alignment shows that 11 beta HSD2 shares 35% identity with 17 beta HSD2, but is only 14% identical with 11 beta HSD1. The 11 beta HSD2 gene is highly expressed in kidney, colon, pancreas and placenta and the message is also present in the ovary, prostate and testis. These data suggest that 11 beta HSD2 plays an important role in modulating mineralocorticoid and glucocorticoid receptor occupancy by glucocorticoids.
Mol Cell Endocrinol 1994 Nov
PMID:Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. 785 16

Incubation of whole LNCaP cells in suspension with tritium labeled cortisol revealed two major and one minor radioactive product. Of the major products, one migrated with an Rf value identical to cortisol (Kendall's compound "F"), and the second migrated with an Rf value similar to nonradioactive cortisone (Kendall's compound "E"); the third minor product comigrated with 21-acetylated cortisol. The conversion of cortisol to cortisone was linear with respect to cell number, and conversion reached a plateau after 120 min of incubation at 37 degrees C. One half of the cortisol was converted to cortisone within 2 h of incubation at 37 degrees C. This conversion was nicotine amide dinucleotide (NAD) dependent. Low levels of transcription activation by cortisol were documented in LNCaP cells transfected with glucocorticoid and androgen responsive mouse mammary tumor virus-bacterial chloramphenicol acetyltransferase chimeric gene (MMTV-CAT). Hormone binding assay and transactivation analysis revealed the presence of a functional mineralocorticoid receptor in LNCaP cells. Treatment of transfectants with F in the presence of carbenoxolone, a potent inhibitor of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), resulted in a two orders of magnitude increase in measurable CAT activity. The addition of the reduced form of nicotine amide dinucleotide (NADH) in the presence of 10(-7) M E stimulated measurable CAT activity in LNCaP cells. In conferring aldosterone specificity in mineralocorticoid target tissues, 11 beta-HSD may have an important role as "gate keeper" in allowing a specific androgen response in hormone responsive LNCaP prostate cancer cells.
J Steroid Biochem Mol Biol 1994 Jun
PMID:11 beta-Hydroxysteroid dehydrogenase and tissue specificity of androgen action in human prostate cancer cell LNCaP. 803 14


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