Disease relevance of NR3C2

• Immunoprecipitation and immunoblot analysis of the recombinant hMR with MR-specific antibodies reveal three major protein bands with molecular masses of 115, 119, and 125 kDa. hMR isoforms show maximal accumulation at 48 h post-infection with the recombinant baculovirus [1].
• Inappropriate activation of the mineralocorticoid receptor (MR) results in renal sodium retention and potassium loss in patients with liver cirrhosis [2].
• Using a murine mammary tumor virus promoter, PIAS1 action was independent of sumoylation whereas with glucocorticoid response element promoter, PIAS1 corepressive action depended on hMR sumoylation status [3].
• The mineralocorticoid receptor (MR) plays a role in congestive heart failure; however, the molecular mechanism(s) remains undefined [4].
• The 11betaHSD2 and MR are also present in the breast tumor cell line PMC42 [5].

Psychiatry related information on NR3C2

• Decreased expression of mineralocorticoid receptor mRNA in the prefrontal cortex in schizophrenia and bipolar disorder [6].
• We hypothesized that the expression of MR would be deficient in the prefrontal cortex of patients with schizophrenia and affective disorders [6].
• Both mental health of humans and animal welfare is likely to be seriously threatened after psychosocial stress, prolonged stress, prenatal stress or postnatal stress, especially when maternal care or social support is absent, because these can chronically dysregulate the central MR/GR balance [7].
• We have now examined both glucocorticoid (GR) and mineralocorticoid (MR) receptor gene expression in individual neurons in human postmortem hippocampus, using in situ hybridization histochemistry in 5 patients with Alzheimer's disease (81 +/- 3 years) and 7 controls (81 +/- 7 years) without neurological disease [8].
• The results suggest that corticosteroid-induced changes in SWS are mediated via MR-like central receptors in humans, whereas changes in REM sleep involve GR [9].

High impact information on NR3C2

• As ENaC activity in the kidney is regulated by the steroid hormone aldosterone acting through the mineralocorticoid receptor, we have screened the mineralocorticoid receptor gene (MLR) for variants and have identified heterozygous mutations in one sporadic and four dominant kindreds [10].
• Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I [10].
• These findings demonstrate that heterozygous MLR mutations cause PHA1, underscore the important role of mineralocorticoid receptor function in regulation of salt and blood pressure homeostasis in humans and motivate further study of this gene for a potential role in blood pressure variation [10].
• They thus permit cortisol to occupy the renal mineralocorticoid receptor and thereby cause sodium retention and hypertension [11].
• This common segment allows the genome to be scanned for related gene products: hMR cDNA for example, was isolated using an hGR hybridization probe [12].

Chemical compound and disease context of NR3C2

• In a congenital deficiency of 11 beta-HSD2, the protective mechanism fails and cortisol gains inappropriate access to mineralocorticoid receptor, resulting in low-renin hypertension and hypokalemia [13].
• The severe form of hypertension caused by the activating S810L mutation in the mineralocorticoid receptor is cortisone related [14].
• A gain of function mutation resulting in the substitution of leucine for serine at codon 810 (S810L) in the human mineralocorticoid receptor (MR) is responsible for early-onset hypertension that is exacerbated in pregnancy [14].
• Pseudohypoaldosteronism (PHA) is characterized by urinary salt-wasting in infancy resulting from a congenital resistance to aldosterone involving the genes for the mineralocorticoid receptor (MR) and the amiloride-sensitive sodium channel (ENaC) [15].
• The interactions of hMR with DEX, TA, DXM, DOC, promegestone (R5020) and methyltrienelone (R1881) were measured by trans-activation of mouse mammary tumor virus long terminal repeat fused to bacterial chloramphenicol acetyltransferase (MMTV-tk-CAT) in gene co-transfection experiments and by cell free hormone binding assay [16].

Biological context of NR3C2

• Mineralocorticoid receptor (MR) controls sodium homeostasis and blood pressure through hormone binding and coactivator recruitment [17].
• In conclusion, these findings indicate that CDCA, and to a lesser extent DCA, by inhibiting 11 beta HSD2, mediate cortisol-dependent nuclear translocation and transcriptional activation of MR and are responsible at least for a part of the sodium retention and potassium excretion observed in patients with biliary obstruction [2].
• Molecular mechanisms underlying mineralocorticoid receptor (MR)-mediated gene expression are not fully understood but seem to largely depend upon interactions with specific coregulators [3].
• Deciphering the unique sumoylation pattern of hMR, which possesses five consensus SUMO-1 binding sites, by combinatorial lysine substitutions, revealed a major impact of sumoylation on hMR properties [3].
• Transient transfections demonstrated that PIAS1 is a corepressor of aldosterone-activated MR transactivation but has no significant effect on human glucocorticoid receptor transactivation [3].

Anatomical context of NR3C2

• Using the MR-specific H10E anti-idiotypic monoclonal antibody, immunoprecipitation of cytosol from recombinant baculovirus-infected Sf9 cells pulse-labeled with 32Pi demonstrated for the first time that the recombinant hMR is highly phosphorylated [1].
• In human kidney, colon, and salivary gland, 11 beta HSD2 protects the MR from glucocorticoid excess in an autocrine fashion [18].
• Immunoperoxidase studies on the mineralocorticoid target tissues, kidney, colon, and parotid gland indicated positive staining in epithelial cells known to express the MR: respectively, renal collecting ducts, surface and crypt colonic epithelial cells, and parotid duct epithelial cells [18].
• MR mRNA abundance in fetal hearts was found to be similar to that in adult kidney and hippocampus [19].
• In the dorsolateral prefrontal cortex Brodmann's area 9 (BA 9), MR mRNA was significantly lower (p<0.05) in all laminae (I-VI) in BP, and in laminae I, III, IV and VI in SZ than in the controls [6].

Associations of NR3C2 with chemical compounds

• Expression studies demonstrate its ability to bind aldosterone with high affinity and to activate gene transcription in response to aldosterone, thus establishing its identity as the human mineralocorticoid receptor (hMR) [20].
• Together, these findings provide critical insights into the molecular basis of hormone binding and coactivator recognition by MR and related steroid receptors [17].
• Here, we report a 1.95 A crystal structure of the MR ligand binding domain containing a single C808S mutation bound to corticosterone and the fourth LXXLL motif of steroid receptor coactivator-1 (SRC1-4) [17].
• The overproduced hMR binds aldosterone with high affinity (Kd = 1.36 nM) and has high affinity for cortisol, cortexolone, and progesterone [1].
• RESULTS: Dex treatment of B-3 and primary cultures demonstrated specific GR, but not mineralocorticoid receptor (MR), activation and phosphorylation [21].

Physical interactions of NR3C2

• Finally, the stoichiometric analysis of the proteins present within the heteromeric MR complex suggests a divergence between this receptor and the GR [22].
• There was no detectable mineralocorticoid receptor binding in endometrial cytosols prepared from patients with a range of 11 beta HSD2 activities [23].
• The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) inactivates glucocorticoids and prevents them from binding to the non-selective mineralocorticoid receptor [24].
• Models of the MR LBD bound to aldosterone and spironolactone were created based on the crystal structure of the progesterone receptor LBD [25].

Enzymatic interactions of NR3C2

• BACKGROUND: 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of hormonally active cortisol to inactive cortisone and is vital for dictating specificity for the mineralocorticoid receptor [26].

Co-localisations of NR3C2

• These results suggest that the 11 beta HSD2 enzyme colocalizes with the mineralocorticoid receptor in the distal nephron where it allows aldosterone to occupy its physiological receptor [27].

Regulatory relationships of NR3C2

• Chenodeoxycholic acid and deoxycholic acid inhibit 11 beta-hydroxysteroid dehydrogenase type 2 and cause cortisol-induced transcriptional activation of the mineralocorticoid receptor [2].
• The hMR is expressed as 9-10 S oligomeric complexes (Stokes radii approximately 67-85 A) that are slightly heavier than the unactivated glucocorticoid receptor and can be converted to smaller 4 S receptor monomers (Stokes radii approximately 25-55 A) by elevated temperature, pH, and ionic strength [1].
• The MR-specific antagonists also down-regulated the expression of G6Pase, while the specific agonist enhanced G6Pase expression [28].
• 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 [29].
• 11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) catalyzes the conversion of cortisol to cortisone and plays an important role in the mammalian kidney in regulating cortisol access to the mineralocorticoid receptor [30].

Other interactions of NR3C2

• Mutations swapping a single residue at position 848 from helix H7 between MR and glucocorticoid receptor (GR) switch their hormone specificity [17].
• Specific interaction between PIAS1 and hMR was confirmed by glutathione-S-transferase pull-down experiments and N-terminal subdomains responsible for physical contacts were delineated [3].
• We provided evidence that PIAS1 conjugated SUMO-1 to hMR both in vitro and in vivo [3].
• In neural cells, PIAS3 exhibited a strong and specific interaction with MR, but not GR, as indicated by mammalian two-hybrid assays and co-immunoprecipitation experiments in vivo [31].
• The human progesterone receptor A-form functions as a transcriptional modulator of mineralocorticoid receptor transcriptional activity [32].

Analytical, diagnostic and therapeutic context of NR3C2

• Finally, indirect immunofluorescence demonstrated that the hMR is expressed primarily as a cytoplasmic protein that can be induced to translocate to the nucleus upon treatment with hormone [1].
• Protein inhibitor of activated signal transducer and activator of transcription 1 interacts with the N-terminal domain of mineralocorticoid receptor and represses its transcriptional activity: implication of small ubiquitin-related modifier 1 modification [3].
• The MR mRNA expression in the post-mortem prefrontal cortex of patients with major depression (MD), bipolar (BP), and schizophrenic (SZ) disorders and non-psychiatric controls (n=15 for each patient group, and n=14 for controls) was determined by in-situ hybridization [6].
• Electrophoretic mobility shift analysis demonstrated that DNA binding of MR occurred only after treatment with aldosterone [22].
• We have identified a new human MR isoform, hMRDelta5,6, resulting from an alternative splicing event skipping exons 5 and 6 of the human MR gene. hMRDelta5,6 mRNAs are expressed in several human tissues at different levels compared with wild-type human MR, as shown by real time PCR [33].

References