Mineralocorticoid receptors and glucocorticoid receptors

1996 ◽  
Vol 45 (6) ◽  
pp. 651-656 ◽  
Author(s):  
John W. Funder
Keyword(s):  
Glucocorticoid Receptors ◽  
Mineralocorticoid Receptors

Steroid hormone stimulation of Na+ transport in A6 cells is mediated via glucocorticoid receptors

1993 ◽  
Vol 264 (4) ◽  
pp. C875-C884 ◽  
Author(s):  
T. J. Schmidt ◽  
R. F. Husted ◽  
J. B. Stokes
Keyword(s):  
Cell Line ◽  
Glucocorticoid Receptors ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Mineralocorticoid Receptors ◽  
Na Transport ◽  
Receptor Complexes ◽  
Binding Forms ◽  
Mineralocorticoid Antagonists

The A6 cell line derived from the toad kidney forms polarized, highly differentiated epithelial monolayers in culture and has been utilized as an experimental model for studying regulation of transepithelial Na+ transport by aldosterone. In the present study we evaluated the specific role(s) of glucocorticoid and mineralocorticoid receptors in mediating this enhanced electrogenic Na+ transport, which was measured experimentally as an increase in short-circuit current (Isc). Our data demonstrate that specific glucocorticoid agonists (100 nM), including RU 28362 and RU 26988, elicit “mineralocorticoid-like” increases in Isc that are blocked by the glucocorticoid antagonist RU 38486 but are unaffected by mineralocorticoid antagonists including RU 28318 and RU 26752. The stimulatory effects of aldosterone (100 nM) were also blocked by RU 38486 and not by mineralocorticoid antagonists. These data extend earlier studies suggesting that in this cell line aldosterone mediates its physiological effects via binding with relatively low affinity (dissociation constant Kd congruent to 25-50 nM) to glucocorticoid receptors, despite the presence of apparently normal mineralocorticoid receptors. Our in vitro biochemical studies also demonstrate that A6 glucocorticoid receptor complexes can be thermally activated or transformed to DNA binding forms which exhibitaltered elution profiles from anion-exchange resins. Thus, based on several criteria, these amphibian glucocorticoid receptors appear very similar to classical mammalian receptors and are capable of mediating all of the stimulatory effects of aldosterone on net Na+ transport.

Mineralocorticoid Receptors and Glucocorticoid Receptors in HPA Stress Responses During Coping and Adaptation

2020 ◽  
Author(s):  
Edo Ronald de Kloet ◽  
Marian Joëls
Keyword(s):  
Stress Response ◽  
Stress Responses ◽  
Coping Style ◽  
Glucocorticoid Receptors ◽  
Memory Storage ◽  
Salt Appetite ◽  
Mineralocorticoid Receptors ◽  
Stress Response System ◽  
Appraisal Processes ◽  
The Brain

The glucocorticoid hormones cortisol and corticosterone coordinate circadian events and are master regulators of the stress response. These actions of the glucocorticoids are mediated by mineralocorticoid receptors (NR3C2, or MRs) and glucocorticoid receptors (NR3C1, or GRs). MRs bind the natural glucocorticoids cortisol and corticosterone with a 10-fold higher affinity than GRs. The glucocorticoids are inactivated only in the nucleus tractus solitarii (NTS), rendering the NTS-localized MRs aldosterone-selective and involved in regulation of salt appetite. Everywhere else in the brain MRs are glucocorticoid-preferring. MR and GR are transcription factors involved in gene regulation but recently were also found to mediate rapid non-genomic actions. Genomic MRs, with a predominant localization in limbic circuits, are important for the threshold and sensitivity of the stress response system. Non-genomic MRs promote appraisal processes, memory retrieval, and selection of coping style. Activation of GRs makes energy substrates available and dampens initial defense reactions. In the brain, GR activation enhances appetitive- and fear-motivated behavior and promotes memory storage of the selected coping style in preparation of the future. Thus, MRs and GRs complement each other in glucocorticoid control of the initiation and termination of the stress response, suggesting that the balance in MR- and GR-mediated actions is crucial for homeostasis and health.

A second enzyme protecting mineralocorticoid receptors from glucocorticoid occupancy

1998 ◽  
Vol 274 (5) ◽  
pp. C1245-C1252 ◽  
Author(s):  
David J. Morris ◽  
Syed A. Latif ◽  
Michael D. Rokaw ◽  
Charles O. Watlington ◽  
John P. Johnson
Keyword(s):  
Glucocorticoid Receptors ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Mineralocorticoid Receptors ◽  
Hydroxylase Activity ◽  
A6 Cells ◽  
Ru 28318 ◽  
The One ◽  
Cytochrome P 450 ◽  
Significant Increment

We have confirmed that A6 cells (derived from kidney of Xenopus laevis), which contain both mineralocorticoid and glucocorticoid receptors, do not normally possess 11β-hydroxysteroid dehydroxgenase (11β-HSD1 or 11β-HSD2) enzymatic activity and so are without apparent “protective” enzymes. A6 cells do not convert the glucocorticoid corticosterone to 11-dehydrocorticosterone but do, however, possess steroid 6β-hydroxylase that transforms corticosterone to 6β-hydroxycorticosterone. This hydroxylase is cytochrome P-450 3A (CYP3A). We have now determined the effects of 3α,5β-tetrahydroprogesterone and chenodeoxycholic acid (both inhibitors of 11β-HSD1) and 11-dehydrocorticosterone and 11β-hydroxy-3α,5β-tetrahydroprogesterone (inhibitors of 11β-HSD2) and carbenoxalone, which inhibits both 11β-HSD1 and 11β-HSD2, on the actions and metabolism of corticosterone and active Na+ transport [short-circuit current ( I sc)] in A6 cells. All of these 11β-HSD inhibitory substances induced a significant increment in corticosterone-induced I sc, which was detectable within 2 h. However, none of these agents caused an increase in I sc when incubated by themselves with A6 cells. In all cases, the additional I sc was inhibited by the mineralocorticoid receptor (MR) antagonist, RU-28318, whereas the original I scelicited by corticosterone alone was inhibited by the glucocorticoid receptor antagonist, RU-38486. In separate experiments, each agent was shown to significantly inhibit metabolism of corticosterone to 6β-hydroxycorticosterone in A6 cells, and a linear relationship existed between 6β-hydroxylase inhibition and the MR-mediated increase in I scin the one inhibitor tested. Troleandomycin, a selective inhibitor of CYP3A, inhibited 6β-hydroxylase and also significantly enhanced corticosterone-induced I sc at 2 h. These experiments indicate that the enhanced MR-mediated I sc in A6 cells may be related to inhibition of 6β-hydroxylase activity in these cells and that this 6β-hydroxylase (CYP3A) may be protecting the expression of corticosterone-induced active Na+ transport in A6 cells by MR-mediated mechanism(s).

Pro- versus Antinociceptive Nongenomic Effects of Neuronal Mineralocorticoid versus Glucocorticoid Receptors during Rat Hind Paw Inflammation

2018 ◽  
Vol 128 (4) ◽  
pp. 796-809 ◽  
Author(s):  
Xiongjuan Li ◽  
Mohammed Shaqura ◽  
Doaa Mohamed ◽  
Antje Beyer ◽  
Shunji Yamada ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mineralocorticoid Receptor ◽  
Glucocorticoid Receptors ◽  
Receptor Expression ◽  
Mineralocorticoid Receptors ◽  
Mineralocorticoid Receptor Antagonist ◽  
Membrane Bound ◽  
Peripheral Sensory ◽  
Nongenomic Effects

Abstract Background In naive rats, corticosteroids activate neuronal membrane–bound glucocorticoid and mineralocorticoid receptors in spinal cord and periphery to modulate nociceptive behavior by nongenomic mechanisms. Here we investigated inflammation-induced changes in neuronal versus glial glucocorticoid and mineralocorticoid receptors and their ligand-mediated nongenomic impact on mechanical nociception in rats. Methods In Wistar rats (n = 5 to 7/group) with Freund’s complete adjuvant hind paw inflammation, we examined glucocorticoid and mineralocorticoid receptor expression in spinal cord and peripheral sensory neurons versus glial using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, immunohistochemistry, and radioligand binding. Moreover, we explored the expression of mineralocorticoid receptors protecting enzyme 11-betahydroxysteroid dehydrogenase type 2 as well as the nociceptive behavioral changes after glucocorticoid and mineralocorticoid receptors agonist or antagonist application. Results Hind paw inflammation resulted in significant upregulation of glucocorticoid receptors in nociceptive neurons of spinal cord (60%) and dorsal root ganglia (15%) as well as mineralocorticoid receptors, while corticosteroid plasma concentrations remained unchanged. Mineralocorticoid (83 ± 16 fmol/mg) but not glucocorticoid (104 ± 20 fmol/mg) membrane binding sites increased twofold in dorsal root ganglia concomitant with upregulated 11-betahydroxysteroid dehydrogenase type 2 (43%). Glucocorticoid and mineralocorticoid receptor expression in spinal microglia and astrocytes was small. Importantly, glucocorticoid receptor agonist dexamethasone or mineralocorticoid receptor antagonist canrenoate-K rapidly and dose-dependently attenuated nociceptive behavior. Isobolographic analysis of the combination of both drugs showed subadditive but not synergistic or additive effects. Conclusions The enhanced mechanical sensitivity of inflamed hind paws accompanied with corticosteroid receptor upregulation in spinal and peripheral sensory neurons was attenuated immediately after glucocorticoid receptor agonist and mineralocorticoid receptor antagonist administration, suggesting acute nongenomic effects consistent with detected membrane-bound corticosteroid receptors.

scholarly journals Mineralocorticoid Receptors: Evolutionary and Pathophysiological Considerations

Endocrinology ◽  
2011 ◽  
Vol 152 (5) ◽  
pp. 1883-1890 ◽  
Author(s):  
Karin S. Kassahn ◽  
Mark A. Ragan ◽  
John W. Funder
Keyword(s):  
Maximum Likelihood ◽  
Glucocorticoid Receptors ◽  
Retinoic Acid Receptor ◽  
Phylogenetic Analyses ◽  
Progesterone Receptors ◽  
Ancestral State ◽  
Mineralocorticoid Receptors ◽  
Ancestral Gene ◽  
Retinoic Acid Receptor Α ◽  
Nuclear Receptor Family

Mineralocorticoid receptors (MR), glucocorticoid receptors (GR), progesterone receptors (PR), and androgen receptors (AR) comprise a closely related subfamily within the human 49-member nuclear receptor family. These receptors and their cognate ligands play major roles in homeostasis, reproduction, growth, and development, despite which their evolution and diversification remains incompletely understood. Several conflicting models have been advanced for the evolution of this subfamily. We have thus undertaken Bayesian and maximum likelihood phylogenetic analyses of this subfamily. The Bayesian consensus and maximum likelihood trees support a basal position for MR, with the PR and AR forming a sister clade. We next performed analyses using topological constraints to directly contrast the likelihood of seven phylogenetic models. In these analyses, three models have similar support: one proposes two sister clades (MR and GR, PR and AR); the other two propose a different subfamily member (MR or GR) to be the first to have diverged. Ancestral state reconstructions at sites critical for physiological function show that the S810L mutation in the MR, which results in the MR being similar to estrogen receptors and the more distantly related retinoic acid receptor-α is likely to reflect the ancestral receptor sequence before the divergence of this subfamily and provides further support for MR having been the first of the subfamily to diverge. Finally, we drew on pathophysiological comparisons to help to distinguish the different models. On the basis of our phylogenetic analyses and pathophysiological considerations, we propose that the MR was the first to diverge from the ancestral gene lineage from which this subfamily derived.

scholarly journals Blocking Mineralocorticoid Receptors Impairs, Blocking Glucocorticoid Receptors Enhances Memory Retrieval in Humans

2012 ◽  
Vol 38 (5) ◽  
pp. 884-894 ◽  
Author(s):  
Ulrike Rimmele ◽  
Luciana Besedovsky ◽  
Tanja Lange ◽  
Jan Born
Keyword(s):  
Memory Retrieval ◽  
Glucocorticoid Receptors ◽  
Mineralocorticoid Receptors

scholarly journals Glucocorticoid receptors function in the pathophysiology of brain hypoxia

2019 ◽  
Vol 73 ◽  
pp. 838-849
Author(s):  
Jan Gregrowicz ◽  
Justyna Rogalska
Keyword(s):  
Glucocorticoid Receptors ◽  
Energy Deficit ◽  
Signalling Pathways ◽  
Main Role ◽  
Mineralocorticoid Receptors ◽  
Neuronal Fate ◽  
Penumbral Region ◽  
The Brain ◽  
Promote Cell Death

Glucocorticoid receptors are ligand-activated transcription factors, which play an important role in the brain, mainly in stress response regulation. There are two types of receptors for glucocorticosteroids: mineralocorticoid receptors (MR) with high-affinity for the ligands and glucocorticoid receptors (GR) with a tenfold lower affinity. Selective activation of the receptors during hypoxia may decide neuronal fate, especially in the hippocampus. Depending on the severity of hypoxia-induced damage, neurons undergo necrosis or apoptosis. In the penumbral region, where neurons die mainly through the process of apoptosis, selective GR activation increases excitotoxicity, interferes with apoptotic signalling pathways and causes energy deficit in the cells, all of which promote cell death. On the other hand, selective MR activation seems to be neuroprotective. It is suggested that the main role of MR in neuroprotection is to regulate the balance between anti- and proapoptotic proteins from bcl-2 family.

scholarly journals Μελέτη της έκφρασης των ισομορφών των υποδοχέων των γλυκοκορτικοειδών (GR) και του ινσουλινομιμητκού αυξητικού παράγοντα - I (IGF-1) σε φυσιολογικό και παθοφυσιολογικό νευρικό ιστό

2018 ◽  
Author(s):  
Ελένη Νικολοπούλου
Keyword(s):  
Growth Factor ◽  
Glucocorticoid Receptors ◽  
Mineralocorticoid Receptors ◽  
Insulin Like Growth Factor

Το στρες οδηγεί τον ανθρώπινο οργανισμό σε σημαντικές αλλαγές της συμπεριφοράς, που συνδέονται και με δομικές αλλαγές σε συγκεκριμένες εγκεφαλικές περιοχές. Κατά την απόκριση του οργανισμού σε ένα στρεσογόνο ερέθισμα, βασικό ρόλο παίζει η παραγωγή των γλυκοκορτικοειδών και η πρόσδεσή τους στους αντίστοιχους υποδοχείς (Glucocorticoid Receptors- GR και Mineralocorticoid Receptors- MR). Οι GR στον εγκέφαλο επηρεάζουν τους μηχανισμούς ανατροφοδότησης για ρύθμιση της απόκρισης του οργανισμού στο στρες. Μεταβολές των GR οδηγούν σε ανωμαλίες της ρύθμισης και υπερέκκριση γλυκοκορτικοειδών. H διαταραγμένη GR-εξαρτώμενη απόκριση στο στρες μπορεί να είναι κρίσιμος παράγοντας στην εμφάνιση νευροψυχιατρικών διαταραχών, όπως η κατάθλιψη, κατά την οποία εμφανίζεται υπερ-κορτιζολεμία. Αναλυτικότερα, 3 περιοχές του εγκεφάλου, ο ιππόκαμπος, ο προ-μετωπιαίος φλοιός και η αμυγδαλή, οι οποίες είναι πλούσιες στην παρουσία GR, ρυθμίζουν την απόκριση του εγκεφάλου στο στρες. Η παρούσα μελέτη προτείνει ότι κατά την εκδήλωση διαταραχών του στρες, δημιουργούνται ανωμαλίες στην απόκριση που προκύπτουν από μεταβολές των GR. Έτσι, θα γίνει ανίχνευση της έκφρασης του GR, σε πρωτεϊνικό επίπεδο, σε τομές ανθρώπινου εγκεφάλου (postmortem) υγιών ατόμων και ατόμων με κατάθλιψη εν ζωή, ώστε να διευκρινιστεί πως η οποιαδήποτε αλλαγή της έκφρασης των GCs που εντοπίζεται σε ψυχιατρικά νοσήματα, σχετίζεται με αλλαγή στη λειτουργία και ρύθμιση του άξονα του στρες (Υποθάλαμος Υπόφυση Επινεφρίδια - ΥΥΕ) και τελικά με την εμφάνιση κατάθλιψης. Ταυτόχρονα, θα γίνει προσδιορισμός της έκφρασης των υποδοχέων GR και MR σε επίπεδο mRNA στα κεντρικά διαμερίσματα του άξονα του στρες, σε πειραματικό μοντέλο με υπέρ- και υπόθυρεοειδισμό και θα προσδιοριστεί η ενεργότητα του GR σε κεντρικούς και περιφερικούς ιστούς (ιππόκαμπος, καρδιά και θύμος αδένας), προκειμένου να τεκμηριωθεί το γεγονός πως σε παθολογικές καταστάσεις με μεταβολές των θυρεοειδικών ορμονών, επηρεάζονται άμεσα τα επιμέρους τμήματα του ΥΥΕ. Η απόκριση του οργανισμού και η προσαρμογή του στο στρες διαμορφώνονται με δράση νευροδιαβιδαστών μορίων, όπως οι αυξητικοί παράγοντες. Ο ινσουλινομιμητικός παράγοντας 1 (Insulin like growth factor 1 - IGF1) είναι ένα μόριο που παίζει σημαντικό ρόλο στη φυσιολογική ανάπτυξη του εγκεφάλου. Έτσι, θα γίνει προσδιορισμός της έκφρασης του IGF-1 σε περιστατικά κακοήθειας στον εγκέφαλο, ώστε να εντοπιστούν μεταβολές τους αυξητικού παράγοντα που σχετίζονται με την εμφάνιση όγκου και να διεξαχθούν χρήσιμα συμπεράσματα. Συμπερασματικά, γίνεται μία προσπάθεια συνολικής και πολύπλευρης προσέγγισης για κατανόηση της λειτουργίας του στρες, μέσα από βασικές αλλαγές που μπορούν να προκληθούν στον οργανισμό. Ο σκοπός είναι να εντοπιστούν αλληλεπιδράσεις στα συνδεόμενα συστήματα του οργανισμού με τελικό αποδέκτη τον ΥΥΕ άξονα με κύριο ρόλο των GR.

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