The brain mineralocorticoid receptor: greedy for ligand, mysterious in function

Reul, Johannes M. H. M.; Gesing, A.; Droste, Susanne K.; Stec, I.; Weber, Anja; Bachmann, Cornelius G.; Bilang-Bleuel, Alicia; Holsboer, Florian; Linthorst, Astrid C E

doi:10.1016/s0014-2999(00)00677-4

Cited by 201 publications

(144 citation statements)

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“…The results of previous studies have shown that DEX induces apoptosis by activating GR: 36 although some earlier reports have suggested that DEX may bind to MR under specific in vitro conditions, there is strong evidence that DEX is predominantly a GR agonist. 45 The apoptotic actions of DEX (10 À5 M) were shown to be significantly attenuated when the MR agonist ALDO (10 À5 M) was added to the culture medium. This finding is consistent with previous results obtained in rats.…”

Section: Discussionmentioning

confidence: 99%

“…To detect GR and MR mRNA transcripts in the cultures, total RNA, free from chromosomal DNA contamination, was isolated (RNAeasy kit, Qiagen, Hilden, Germany) and reverse transcribed with SUPERSCRIPTt II RNA H-reverse transcriptase (Life Technologies) using custom-synthesized oligo-dT [12][13][14][15][16][17][18] primers (MWG Biotech, Ebersberg, Germany). Published primers 24 were used and amplification conditions were denaturation for 40 s at 941C, annealing for 1 min at 621C (MR) or 401C (GR), and primer extension for 2 min at 721C; optimal amplifications of MR and GR mRNA were achieved after 35 and 25 cycles, respectively.…”

Section: Reverse-transcriptase Pcrmentioning

confidence: 99%

“…15 MR and GR both bind cortisol/corticosterone, albeit with differing affinities: whereas GR become occupied by corticosteroid levels in the high physiological range, MR appear to be tonically active under basal levels of HPA activity, and there is evidence that activity of the two receptors is coordinated so as to maintain endocrinological and behavioral balance. 1,16,17 We previously proposed that the relative occupation of MR and GR also contributes to maintenance of hippocampal cell numbers, since activation of MR counteract deleterious GC actions on neuronal survival. 11,13,14 Indeed, the results of earlier studies suggest that MR occupation may be essential for the survival of dentate granule neurons.…”

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confidence: 99%

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Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation

et al. 2005

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An important question arising from previous observations in vivo is whether glucocorticoids can directly influence neuronal survival in the hippocampus. To this end, a primary postnatal hippocampal culture system containing mature neurons and expressing both glucocorticoid (GR) and mineralocorticoid (MR) receptors was developed. Results show that the GR agonist dexamethasone (DEX) targets neurons (microtubule-associated protein 2-positive cells) for death through apoptosis. GR-mediated cell death was counteracted by the MR agonist aldosterone (ALDO). Antagonism of MR with spironolactone ([7a-(acetylthio)-3-oxo-17a-pregn-4-ene-21 carbolactone] (SPIRO)) causes a dose-dependent increase in neuronal apoptosis in the absence of DEX, indicating that nanomolar levels of corticosterone present in the culture medium, which are sufficient to activate MR, can mask the apoptotic response to DEX. Indeed, both SPIRO and another MR antagonist, oxprenoate potassium ((7a,17a)-17-hydroxy-3-oxo-7-propylpregn-4-ene-21-carboxylic acid, potassium salt (RU28318)), accentuated DEX-induced apoptosis. These results demonstrate that GRs can act directly to induce hippocampal neuronal death and that demonstration of their full apoptotic potency depends on abolition of survival-promoting actions mediated by MR. Molecular Psychiatry (2005) 10, 790-798.

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Section: Discussionmentioning

confidence: 99%

Section: Reverse-transcriptase Pcrmentioning

confidence: 99%

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Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation

et al. 2005

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“…Both MR and glucocorticoid receptors (GR) are found in the brain. MR is found primarily in the limbic areas, such as the hippocampus, whereas the GR is more widely expressed [48].…”

Section: Mineralocorticoids and Neuronsmentioning

confidence: 99%

Aldosterone: good guy or bad guy in cerebrovascular disease?

Rigsby

Cannady

Dorrance

2005

Trends in Endocrinology & Metabolism

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Stroke is a leading cause of disability in the Western world, yet the choices for therapeutic intervention are few. The complex role played by aldosterone in the pathogenesis of stroke is beginning to emerge. Chronic mineralocorticoid receptor (MR) blockade reduces the incidence of hemorrhagic strokes and the severity of damage caused by ischemic strokes. This appears to be a vascular phenomenon because MR blockade increases vessel lumen diameter, which presumably increases blood flow and perfusion of the tissue to reduce ischemic damage. However, the vascular protection afforded by MR antagonism is at odds with the results seen within the brain, where MR activation is required for neuronal survival. Both of these divergent effects have possible therapeutic implications for stroke.

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“…Thus, it has been suggested that the adaptive function of the HPA axis is critically dependent on glucocorticoid feedback mechanisms to dampen the stressor-induced activation of the HPA axis and to shut off further glucocorticoid secretion (Jacobson and Sapolsky, 1991). The MR is found only in the brain and in epithelial cells of the kidney, the colon, and exocrine glands (Kretz et al, 2001) (Reul et al, 2000).…”

Section: Corticosteroid Receptorsmentioning

confidence: 99%