Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity.

Krozowski, Zygmunt; Funder, John W.

doi:10.1073/pnas.80.19.6056

Cited by 445 publications

(197 citation statements)

References 25 publications

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“…The GR and MR show a high degree of colocalization in the hippocampus (Arriza et al, 1988;de Kloet et al, 1998). Because the MR has ϳ10-fold higher affinity for CORT than the GR, hippocampal MR responds strongly to CORT (Krozowski and Funder, 1983;Beaumont and Fanestil, 1988;Rupprecht et al, 1993). Thus, in the hippocampus, this one compound, CORT, serves to regulate the two signaling pathways via the MR and GR (Reul and de Kloet, 1985;Pearce and Yamamoto, 1993;Kawata, 1995).…”

Section: Introductionmentioning

confidence: 99%

Visualization of Glucocorticoid Receptor and Mineralocorticoid Receptor Interactions in Living Cells with GFP-Based Fluorescence Resonance Energy Transfer

Nishi¹,

Tanaka²,

Matsuda³

et al. 2004

J. Neurosci.

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Adrenal corticosteroids readily enter the brain and exert markedly diverse effects, including stress responses in the target neural cells via two receptor systems, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). It has been shown that the GR and MR are highly colocalized in the hippocampus. Given the differential action of the MR and GR in the hippocampal region, it is important to elucidate how these receptors interact with each other in response to corticosteroids. We investigated the heterodimerization of the MR and GR with green fluorescent protein-based fluorescence resonance energy transfer (FRET) microscopy in living cells with spatiotemporal manner. FRET was evaluated in three ways: (1) ratio imaging; (2) emission spectra; and (3) acceptor photobleaching. FRET analysis demonstrated that cyan fluorescent protein-GR and yellow fluorescent protein-MR form heterodimers after corticosterone (CORT) treatment both in the nucleus of cultured hippocampal neurons and COS-1 cells, whereas they do not form heterodimers in the cytoplasm. The content of the GR-MR heterodimer was higher at 10 Ϫ6 M CORT than at 10 Ϫ9 M CORT and reached a maximum level after 60 min of CORT treatment in both cultured hippocampal neurons and COS-1 cells. The distribution pattern of heterodimers in the nucleus of cultured hippocampal neurons was more restricted than that in COS-1 cells. The present study using mutant fusion proteins in nuclear localization signal showed that these corticosteroid receptors are not translocated into the nucleus in the form of heterodimers even after treatment with ligand and thus allow no heterodimerization to take place in the cytoplasm. These results obtained with FRET analyses give new insights into the sites, time course, and effects of ligand concentration on heterodimersization of the GR and MR.

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Section: Introductionmentioning

confidence: 99%

Visualization of Glucocorticoid Receptor and Mineralocorticoid Receptor Interactions in Living Cells with GFP-Based Fluorescence Resonance Energy Transfer

Nishi¹,

Tanaka²,

Matsuda³

et al. 2004

J. Neurosci.

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“…Mineralocorticoid receptors in preparations of kidney or hippocampus, for example, bind aldosterone and the physiologic glucocorticoid cortisol (in rats, corticosterone) with equal affinity (2,3). The circulating levels of glucocorticoids are very much higher than those of aldosterone; what enables aldosterone to occupy mineralocorticoid receptors in physiologic target tissues is the enzyme hydroxysteroid dehydrogenase ( 1 lI3HSD), which metabolizes cortisol and corticosterone to their receptor-inactive 11 -keto congeners cortisone and 11 -dehydrocorticosterone.…”

Section: Introductionmentioning

confidence: 99%

Mineralocorticoids, hypertension, and cardiac fibrosis.

et al. 1994

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Uninephrectomized rats drinking 1% sodium chloride were given aldosterone (Aldo, 0.75 gg/h, subcutaneous Is.c.I infusion), deoxycorticosterone (DOC, 20 mg/wk, s.c.), corticosterone (B, 2 mg/d, s.c.), or the antiglucocorticoid-antiprogestin RU486 (2 mg/d, s.c.) for 8 wk, and hemodynamic and tissue responses were compared with a non-steroid-treated control group. Aldo and DOC markedly increased systolic BP and caused considerable (40-50%) cardiac hypertrophy; B and RU486 caused neither hypertension nor cardiac hypertrophy. Measurements of ventricular cross-sectional areas showed hypertrophy due to an increase in mass of the left ventricle only. Cardiac hydroxyproline concentration was increased considerably by Aldo and DOC, to a lesser degree by RU486, and not by B. Aldo markedly elevated left ventricular interstitial collagen (2.5-fold vs control, P < 0.01 vs all groups); other steroid treatments also increased interstitial collagen over control (DOC X 1.8-, RU486 X 1.6-, B X 13-fold), with identical responses for right and left ventricles (r = 0.94). A different pattern of perivascular fibrosis was noted; DOC elevated perivascular collagen (2.1-fold vs control, P < 0.01 vs all other groups); RU486 raised levels 1.4-fold vs control, but neither Aldo nor B significantly affected perivascular collagen. These data are consistent with interstitial cardiac fibrosis reflecting type I (mineralocorticoid) receptor occupancy by administered Aldo or DOC, or by elevated endogenous B after type II (glucocorticoid) receptor blockade after RU486 administration; perivascular fibrosis may reflect a composite response after type I receptor agonist/type II glucocorticoid receptor antagonist occupancy. (J. Clin. Invest. 1994.93:2578-2583

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“…The mineralocorticoid aldosterone and the glucocorticoids cortisol in humans and corticosterone in rodents have the same in vitro affinity for the nonselective mineralocorticoid receptor (MR) (1). The MR is normally protected from glucocorticoid occupation by the enzyme 11␤-hydroxysteroid dehydrogenase (11␤HSD), which converts cortisol to the receptor inactive cortisone (2).…”

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confidence: 99%

Modulation of Renal Calcium Handling by 11β-Hydroxysteroid Dehydrogenase Type 2

Ferrari

Bianchetti²,

Sansonnens³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Reduced concentration of serum ionized calcium and increased urinary calcium excretion have been reported in primary aldosteronism and glucocorticoid-treated patients. A reduced activity of the 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) results in overstimulation of the mineralocorticoid receptor by cortisol. Whether inhibition of the 11␤HSD2 by glycyrrhetinic acid (GA) may increase renal calcium excretion is unknown. Serum and urinary electrolyte and creatinine, serum ionized calcium, urinary calcium excretion, and the steroid metabolites (THFϩ5␣THF)/THE as a parameter of 11␤HSD2 activity were repeatedly measured in 20 healthy subjects during baseline conditions and during 1 wk of 500 mg/d GA. One week of GA induced a maximal increment of 93% in (THFϩ5␣THF)/THE. Ambulatory BP was significantly higher at day 7 of GA than at baseline (126/77 Ϯ 10/7 versus 115/73 Ϯ 8/6 mmHg; P Ͻ 0.001 for systolic; P Ͻ 0.05 for diastolic). During GA administration, serum ionized calcium decreased from 1.26 Ϯ 0.05 to 1.18 Ϯ 0.04 mmol/L (P Ͻ 0.0001), and absolute urinary calcium excretion was enhanced from 29.2 Ϯ 3.6 to 31.9 Ϯ 3.1 mol/L GFR (P Ͻ 0.01). Fractional calcium excretion increased from 2.4 Ϯ 0.3 to 2.7 Ϯ 0.3% (P Ͻ 0.01) and was negatively correlated to the fractional sodium excretion during GA (R ϭ Ϫ0.35; P Ͻ 0.001). Moreover, serum potassium correlated positively with serum ionized calcium (R ϭ 0.66; P Ͻ 0.0001). Inhibition of 11␤HSD2 activity is sufficient to significantly increase the fractional excretion of calcium and decrease serum ionized calcium, suggesting decreased tubular reabsorption of this divalent cation under conditions of renal glucocorticoid/mineralocorticoid excess. The likely site of steroid-regulated renal calcium handling appears to be the distal tubule.

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Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity.

Cited by 445 publications

References 25 publications

Visualization of Glucocorticoid Receptor and Mineralocorticoid Receptor Interactions in Living Cells with GFP-Based Fluorescence Resonance Energy Transfer

Visualization of Glucocorticoid Receptor and Mineralocorticoid Receptor Interactions in Living Cells with GFP-Based Fluorescence Resonance Energy Transfer

Mineralocorticoids, hypertension, and cardiac fibrosis.

Modulation of Renal Calcium Handling by 11β-Hydroxysteroid Dehydrogenase Type 2

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