30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The brain mineralocorticoid receptor: a saga in three episodes

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   Figure 1

   Basolateral cell excitability is differentially affected by waves of stress hormones, depending on the concentrations. (A) Averaged responses over time during and >2 h after a wave of the β-agonist isoproterenol (ISO), administered at a low concentration. Bars represent the frequency of miniature excitatory postsynaptic currents (mEPSCs; mean + s.e.m., in Hz), based on n = 5–12 cells per bar. In this panel as well as panels B, C, D and E, the application scheme is shown at the bottom. The ISO and/or corticosterone (CORT) concentration indicated was perfused during the block-period marked by the vertical black lines in the schemes. The stippled line indicates the actual ISO and/or CORT concentration estimated from samples extracted in control experiments with a dye in the same set-up. (B) Averaged responses over time during and after the waves of stress hormones mimicking moderate stress. Based on n = 55–11 cells per bar. (C) Averaged responses over time during and after waves of stress hormones mimicking severe stress conditions. Based on n = 88–15 cells per bar. (D) Averaged responses over time during and after waves of CORT similar as used in B. Based on n = 55–10 cells per bar. (E) Averaged responses over time during and after waves of CORT similar as used in C. Based on n = 44–11 cells per bar. In all cases (panels A, B, C, D and E), the shading of the bars corresponds to the level of significance of the change in mEPSC frequency compared to baseline. Bars during the first block were compared to baseline with a paired Student’s t test; values of later bars were compared with an unpaired Student’s t-test (in all cases uncorrected for multiple testing). Black bars: P > 0.1 compared to baseline; striped bars: P < 0.05 based on paired testing with baseline; dark gray bars: P < 0.05 based on unpaired testing with baseline; light gray bars: P < 0.01 based on unpaired testing with baseline. The data indicate that moderate-to-high concentrations rapidly increase excitability, via β-adrenergic and MR-mediated effects. In the longer term, changes in excitability strongly depend on the hormone concentrations: with low-to-moderate concentrations excitability is suppressed, whereas high concentrations result in prolonged over-excitation. The latter reflects combined late effects through β-adrenoceptors and (most likely) GRs. Data from Karst & Joëls (2016).
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   Figure 2

   Genomic distribution of glucocorticoid receptor-binding sites in rat hippocampus genome. (A) Distribution of GBS relative to the nearest gene, resulting in regions that lie within or outside genes. The black bar represents a gene, showing that 39% of the GBS are located within genes. The GBS that are located upstream or downstream from the nearest gene are divided into 3 bins: within 10 kb, between 10 and 100 kb and more than 100 kb from a gene. (B) Pie chart showing the location of intragenic GBS within annotated RefSeq genes, divided into 5′-UTR (exon or intron), intron, exon, intron/exon overlap, and 3′-UTR (exon or intron) regions. Reproduced, with permission, from Polman JA, de Kloet ER & Datson NA, Endocrinology, volume 154, pages 1832–1844, 2013, Two populations of glucocorticoid receptor-binding sites in the male rat hippocampal genome. Copyright 2013, The Endocrine Society. See also van Weert et al. (2017).
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   Figure 3

   Ligand structure determines the nuclear mobility of the MR. A range of natural and synthetic agonists (black bars) and antagonists (red bars) were tested for their effect on the intranuclear mobility of the MR by both SMM (A) and FRAP (B and C) analysis. The MR and GR share several agonists, but the binding and functional characteristics differ. Indeed, a weak agonist for the GR, corticosterone (cort), which gave a very mobile GR, instead leads to a low mobility for the MR. A large bound fraction (SMM; white bars and FRAP; white and light grey bars combined) a low diffusion coefficient (in µm²/s, written within its corresponding bar in A) and long immobilization times (C). Of all functional steroid side groups, only the 18-keto (18=O) group appears to affect the mobility of the MR. SMM: n = 20, FRAP: n = 30. Data represented as total fit ± s.e.m. (of 3 separate PICS analyses) for SMM and as average of top 10% fits ± s.e.m. for FRAP. Aldo, aldosterone; csol, cortisol; dex, dexamethasone; DOC, deoxycorticosterone; epler, eplerenone; spiro, spironolactone. Reproduced under the terms of the original Creative Commons Attribution License, from Groeneweg FL, van Royen ME, Fenz S, Keizer VI, Geverts B, Prins J, de Kloet ER, Houtsmuller AB, Schmidt TS & Schaaf MJ, 2014, Quantitation of glucocorticoid receptor DNA-binding dynamics by single-molecule microscopy and FRAP. PLoS ONE, volume 14, e90532.

• © 2017 Society for Endocrinology