PubMed Health⌕ Search

Biomedical subjects

O C Meijer

Publications and source records attributed to O C Meijer.

At least 37 records · Page 2Linked to original sources
PubMed2000

Plasma membrane calcium pump isoform 1 gene expression is repressed by corticosterone and stress in rat hippocampus.

Glucocorticoids (GCs) are critical to learning and memory, in large part because of their actions in the hippocampus. Chronic high levels of GCs have profound effects on hippocampal structure and function and can even result in irreversible neurodegeneration. Hippocampal GC actions are mediated by intracellular receptors that modulate the transcription of specific target genes. In a screen for genes repressed by GCs in rat hippocampus, we identified plasma membrane calcium pump isoform 1 (PMCA1), a plasma membrane calcium ATPase. In Northern blots, PMCA1 was repressed approximately 33% after a high, but not a low dose of the GC, corticosterone (B), suggesting glucocorticoid (but not mineralocorticoid) receptor-mediated repression. Furthermore, in situ hybridization demonstrated that B significantly downregulated PMCA1 mRNA in all brain regions examined. Repression of PMCA1 was also observed in cultured hippocampal neurons, but only when the cells were in the differentiated state. Stress also repressed PMCA1 expression in hippocampus of adrenal-intact animals, and a clear inverse correlation between B level and PMCA1 mRNA could be discerned. However, other non-B-dependent factors appeared to be involved in the response of PMCA1 to stress because, unlike exogenous B, cold stress did not repress PMCA1 in brain regions other than hippocampus. Moreover, in the presence of constant B (B-replaced, adrenalectomized animals), cold stress led to increased hippocampal PMCA1 expression. These observations suggest that repression of PMCA1 represents one molecular mechanism by which corticosteroids regulate Ca(2+) homeostasis and hence influence neuronal activity. Moreover, other stress-related neurohumoral factors appear to counter the repressive effects of B. Defects in the balance between GC-mediated and non-GC-mediated effects on PMCA1 expression may have adverse effects on neuronal function and ultimately result in irreversible neuronal damage.

Adrenalectomy↗
PubMed2000

The Yin and Yang of nuclear receptors: symposium on nuclear receptors in brain, Oegstgeest, The Netherlands, 13-14 April 2000.

Novel aspects of nuclear receptors and their function in brain were discussed at a recent Symposium in Oegstgeest, The Netherlands. Presentations covered the diversity of these receptors, their target genes, proteins involved in transcriptional regulation, functional consequences of nuclear receptor activation and their relevance for human pathology. By elucidating the signalling pathway of nuclear receptors in brain, potential targets for therapeutic treatment of brain disorders can be identified.

Brain↗
PubMed2000

Transcriptional repression of the 5-HT1A receptor promoter by corticosterone via mineralocorticoid receptors depends on the cellular context.

The diverse effects of the corticosteroid hormones are mediated in large measure by the mineralocorticoid and glucocorticoid receptors, two closely related members of the nuclear receptor superfamily. In the brain, corticosteroids regulate neuronal excitability and responses to neurotransmitters in a cell type-specific manner. The 5-HT1A receptor, for example, is highly expressed in the hippocampus and raphe but transcription is repressed by corticosterone (the principal glucocorticoid in rodents) only in hippocampus. We have used transient transfection of cultured cells to study the transcriptional regulation of the 5-HT1A receptor promoter by activators and repression by glucocorticoids. We find that transcription factors Sp1 and NF-kB subunit p65, both of which are coexpressed in hippocampus with the 5-HT1A receptor in vivo, synergistically activate a reporter driven by receptor 5'-flanking region. Primer extension data suggest that the multiple transcription initiation sites used in reporter gene transcription correlate with those used in transcription of the endogenous gene which has a TATA-less promoter. Repression of transcription by corticosteroids was found to be mediated by both mineralocorticoid and glucocorticoid receptors, but not identically. While glucocorticoid receptors potently inhibited both p65- and p65/Sp1-stimulated transcription, repression via mineralocorticoid receptors (MR) depended on the transcriptional activators that were present: p65-stimulated reporter activity was not repressed via MR, whereas a similar level of transcription resulting from synergistic activation by p65/Sp1-stimulation was repressed via MR. The context-dependence of these MR-mediated effects provides a model for the cell-type and state-dependent actions of corticosterone in the brain.

Animals↗
PubMed2000

Role of SGK in mineralocorticoid-regulated sodium transport.

Mineralocorticoids stimulate electrogenic Na+ transport in tight epithelia by altering the transcription of specific genes. Although the earliest mineralocorticoid effect is to increase the activity of the epithelial sodium channel (ENaC), ENaC mRNA and protein levels do not change. Instead, physiologic observations suggest that a mineralocorticoid target gene(s) encodes an ENaC regulator(s). To begin to identify and characterize mineralocorticoid-regulated target genes, we used suppression-subtractive hybridization to generate a cDNA library from A6 cells, a stable cell line of Xenopus laevis of distal nephron origin. A serine-threonine kinase, SGK, was identified from this screen. Sequence comparison revealed that frog, rat, and human SGK are 92% identical and 96% similar at the amino acid level. SGK mRNA was confirmed by Northern blot to be strongly and rapidly corticosteroid stimulated in A6 cells. In situ hybridization revealed that SGK was strongly stimulated by aldosterone in rat collecting duct but not proximal tubule cells. Low levels of SGK were present in rat glomeruli, but SGK was unregulated in this structure. Finally, SGK stimulated ENaC activity approximately sevenfold when coexpressed in Xenopus laevis oocytes. These data suggest that SGK is an important mediator of aldosterone effects on Na+ transport in tight epithelia. In view of the existence of SGK homologues in invertebrates, it is interesting to speculate that SGK is an ancient kinase that was adapted to the control of epithelial Na+ transport by early vertebrates as they made the transition from a marine to a freshwater environment.

Amino Acid Sequence↗
PubMed2000

Brain mineralocorticoid receptors and centrally regulated functions.

Mineralocorticoid receptors (MRs) expressed in limbic neurons, notably of hippocampus, retain both aldosterone and corticosterone. Basal concentrations of corticosterone already substantially occupy the limbic MR type, suggesting that in hippocampal neurons, MR activity rather than ligand bioavailability is rate limiting. The periventricular region expresses MRs involved in the control of salt homeostasis, which are aldosterone selective because of the presence of 11beta-hydroxysteroid dehydrogenase. MR is in hippocampal CA1, CA2, and dentate gyrus colocalized with glucocorticoid receptors (GRs). Both receptor types mediate in a coordinate manner the corticosterone action on information processing critical for behavioral adaptation and associated neuroendocrine responses to stress. MRs operate in proactive mode determining the sensitivity of the stress response system, while GRs facilitate recovery from stress in reactive mode. On the neuronal level, MR-mediated action maintains a stable excitatory tone and attenuates the influence of modulatory signals. In contrast, GR-mediated effects suppress excitability transiently raised by excitatory stimuli. MR is also involved in control of autonomic outflow and volume regulation. This was demonstrated by the effect of an MR antagonist, which was administered centrally, because mdr P-glycoproteins hamper the access of synthetic steroids to the brain. The MR antagonist attenuates pressor responses to a stressor, such as experienced during tail sphygmography. Diuresis and urinary electrolyte excretion are increased after the MR antagonist, but this effect is abolished after bilateral denervation of the kidney. It is presently unknown in which brain cells the MR-mediated effects on these aspects of central cardiovascular regulation occur.

Animals↗
PubMed2000

Differential expression and regional distribution of steroid receptor coactivators SRC-1 and SRC-2 in brain and pituitary.

Members of the p160 family of steroid receptor coactivator proteins mediate the stimulatory effects on gene transcription brought about by nuclear receptors, which comprise all steroid receptors. Using in situ hybridization we have examined the neuroanatomical distribution of the messenger RNAs (mRNAs) for two functionally distinct splice variants of Steroid Receptor Coactivator 1 (SRC-1/NCoA-1) and of Steroid Receptor Coactivator 2 (SRC-2/NCoA-2/GRIP-1/TIF-2). Transcripts encoding these coactivators show highly differential expression patterns. SRC-2 mRNA is expressed at very low levels in brain, but shows expression in the anterior pituitary. SRC-la and le mRNA are expressed in many brain areas, including hippocampus, amygdala, hypothalamus, basal ganglia, and isocortex. Striking differences between SRC-1a and le expression were observed in several brain nuclei. Relative levels of SRC-1a mRNA were much higher in anterior pituitary, and the arcuate, paraventricular and ventromedial nucleus of the hypothalamus, the locus coeruleus and the trigeminal motor nucleus, all important targets of steroid hormones in the brain. SRC-le mRNA showed modest elevation of relative expression in the caudal nucleus accumbens (shell), basolateral amygdala, and some thalamic nuclei. The differential and uneven neuroanatomical distribution of these coactivators may underlie diversity and cell-specificity of steroid receptor mediated signals in the brain.

Amygdala↗
PubMed1999

Epithelial sodium channel regulated by aldosterone-induced protein sgk.

Sodium homeostasis in terrestrial and freshwater vertebrates is controlled by the corticosteroid hormones, principally aldosterone, which stimulate electrogenic Na+ absorption in tight epithelia. Although aldosterone is known to increase apical membrane Na+ permeability in target cells through changes in gene transcription, the mechanistic basis of this effect remains poorly understood. The predominant early effect of aldosterone is to increase the activity of the epithelial sodium channel (ENaC), although ENaC mRNA and protein levels do not change initially. Rather, the open probability and/or number of channels in the apical membrane are greatly increased by unknown modulators. To identify hormone-stimulated gene products that modulate ENaC activity, a subtracted cDNA library was generated from A6 cells, a stable cell line of renal distal nephron origin, and the effect of candidates on ENaC activity was tested in a coexpression assay. We report here the identification of sgk (serum and glucocorticoid-regulated kinase), a member of the serine-threonine kinase family, as an aldosterone-induced regulator of ENaC activity. sgk mRNA and protein were strongly and rapidly hormone stimulated both in A6 cells and in rat kidney. Furthermore, sgk stimulated ENaC activity approximately 7-fold when they were coexpressed in Xenopus laevis oocytes. These data suggest that sgk plays a central role in aldosterone regulation of Na+ absorption and thus in the control of extracellular fluid volume, blood pressure, and sodium homeostasis.

Aldosterone↗
PubMed1998

Flesinoxan treatment reduces 5-HT1A receptor mRNA in the dentate gyrus independently of high plasma corticosterone levels.

Flesinoxan acts as a full 5-HT1A receptor agonist and displays anxiolytic and anti-depressant properties. 5-HT1A receptor agonists, including flesinoxan, increase corticosterone (B) levels in the blood and reduces 5-HT1A receptor mRNA expression in the hippocampus. In this study, we examined whether the 5-HT1A receptor downregulation induced by flesinoxan involves corticosterone control of 5-HT1A receptor gene transcription. In experiment I, intact male Wistar rats (180-200 g) were treated with flesinoxan (1.0, 3.0 and 10 mg/kg bw, sc) or vehicle and decapitated 3 h later. Flesinoxan administration resulted in a significant, dose-dependent downregulation of 5-HT1A receptor mRNA in the dentate gyrus and dorsal raphe nucleus. In experiment II, rats were sham-operated and implanted with a cholesterol pellet (100 mg) or were adrenalectomized and implanted with a corticosterone pellet (20 mg corticosterone + 80 mg cholesterol). Flesinoxan injection also caused a dose-dependent decrease of 5-HT1A mRNA in the dentate gyrus of adrenalectomized animals with corticosterone replacement. There was no effect in the dorsal raphe nucleus. In experiment III, adrenalectomized and adrenalectomized + corticosterone rats were sc injected with flesinoxan (10 mg/kg bw) or vehicle, and flesinoxan appeared to downregulate 5-HT1A receptor expression in the dentate gyrus independently of corticosterone as well. No significant effects were observed in the dorsal raphe nucleus. It is concluded that flesinoxan reduces 5-HT1A receptor expression in the dentate gyrus both through homologous downregulation and a corticosterone-mediated effect on the serotonergic (5-HT) system.

Animals↗
PubMed1998

Acute rise in corticosterone facilitates 5-HT(1A) receptor-mediated behavioural responses.

Corticosterone influences 5-HT1A receptor-mediated responses in the rat hippocampus in vitro: activation of the high affinity mineralocorticoid receptor suppresses 5-HT1A receptor-mediated hyperpolarization, while subsequent activation of lower affinity glucocorticoid receptors enhances the effect of 5-HT. We have tested whether a similar effect of corticosterone exists in vivo. In intact rats, a systemic injection of the specific 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), led to increased locomotion and to a less persistent search strategy in the free swim trial of the Morris water maze test. Adrenalectomized rats with a corticosterone-pellet implanted as replacement received an injection of vehicle (predominant mineralocorticoid receptor occupation) or a high dose of corticosterone (both corticosteroid receptor types occupied) 1 h before injection of 8-OH-DPAT. The effect on search strategy, but not on locomotor activity, was less in animals with low corticosterone levels. The results suggest that hippocampal 5-HT1A receptor-mediated responses in vivo are attenuated during predominant activation of the mineralocorticoid receptor and increased after additional transient activation of the glucocorticoid receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice.

Mice with a genetic disruption of the multiple drug resistance (mdr1a) gene were used to examine the effect of the absence of its drug-transporting P-glycoprotein product from the blood-brain barrier on the distribution and cell nuclear uptake of [3H]-dexamethasone in the brain. [3H]-dexamethasone (4 microg/kg mouse) was administered s.c. to adrenalectomized mdr1a (-/-) and mdr1a (+/+) mice. One hour later, the mice were decapitated, and the radioactivity was measured in homogenates of cerebellum, blood, and liver following extraction of the radioactive steroid. The frontal brain was cut in sections for autoradiography. In the cerebellum of the mdr1a mutants, the amount of [3H]-dexamethasone relative to blood was about 5-fold higher than observed in the controls, whereas the ratio in blood vs. liver was not different. Using autoradiography, it was found that brain areas expressing the glucocorticoid receptor (GR) in high abundance, such as the hippocampal cell fields and the paraventricular nucleus (PVN), showed a 10-fold increase in cell nuclear uptake of radiolabeled steroid. The amount of retained steroid increased toward levels observed in the pituitary, which contains a similar density of GRs. The [3H]-dexamethasone concentration in pituitary was not affected by mdr1a gene disruption. The GR messenger RNA expression pattern in hippocampus was not different between the wild types and mdr1a mutants, which rules out altered receptor expression as a cause of the enhanced dexamethasone uptake. In conclusion, the present study demonstrates that the brain is resistant to penetration by dexamethasone because of mdr1a activity at the level of the blood-brain barrier. The data support the concept of a pituitary site of action of dexamethasone in blockade of stress-induced ACTH release. Dexamethasone poorly substitutes for depletion of the endogenous glucocorticoid from the brain and therefore, in this tissue, may cause a condition resembling that of adrenalectomy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Corticosterone and serotonergic neurotransmission in the hippocampus: functional implications of central corticosteroid receptor diversity.

The activity of the hippocampus is modulated by a serotonergic projection from the midbrain. Corticosteroids regulate the activity of this raphe-hippocampal system in various ways. These effects are differentially mediated via two types of central corticosteroid receptor types, the high-affinity mineralocorticoid receptor (MR), and the lower affinity glucocorticoid receptor (GR). Under physiological fluctuations of corticosteroid concentrations, predominantly MR-mediated effects suppress the activity of the raphe-hippocampal system, notably serotonin (5-HT)1A receptor-related activity: 5-HT1A receptors are down-regulated, and the cellular response to 5-HT1A receptor activation is attenuated. Transiently increased concentrations of corticosteroids, as induced by stress, result in combined occupation of both MR and GR, and allow increased activity of the raphe-hippocampal system. Stimulatory actions of corticosteroids involving GR occupation include increased responsiveness of hippocampal neurons to 5-HT1A receptor stimulation, attenuated autoinhibition of 5-HT, and a permissive effect on stress-induced increases in 5-HT release. Under (pathological) conditions of chronically elevated corticosteroid concentrations, however, serotonergic neurotransmission is impaired. Human depression is an important example of a condition of combined hypercorticism and an apparent hypoactivity of serotonergic transmission. Deficiency of brain GR function may be genetically determined or acquired by stress. It is proposed that the balance of MR/GR activation can be altered by chronic (stress-related) changes of corticosteroid concentrations, in combination with glucocorticoid feedback resistance. Such an imbalance would lead to a relative dominance of MR-mediated suppressive effects on the activity of the raphe-hippocampal system, which may be a biologically relevant aspect of depression.

Corticosterone↗
PubMed1997

Regulation of hippocampal 5-HT1A receptor mRNA and binding in transgenic mice with a targeted disruption of the glucocorticoid receptor.

Corticosterone is known to suppress levels of 5-HTA(1A) receptor mRNA in rat hippocampus. We describe hippocampal 5-HT(1A) receptor mRNA regulation in mice that have a targeted disruption of the glucocorticoid receptor gene. 5-HT(1A) receptor mRNA levels as well as binding of [3H]8-OH-DPAT, were measured in the hippocampus of heterozygous and homozygous GR-deficient mice and in wild-type control mice. The effect of adrenalectomy in wild-type mice and heterozygous knockouts was also studied. We hypothesized that if the glucocorticoid receptor is important as a mediator of the suppressive effect of corticosterone, this would be revealed by changed (enhanced) expression of 5-HT(1A) receptor mRNA in mice with a genetically changed glucocorticoid receptor status. It was found that 5-HT(1A) receptor mRNA levels and 5-HT(1A) receptor binding were not different in GR-deficient mice. The 5-HT(1A) receptor mRNA levels were responsive to corticosterone, as adrenalectomy led to increased levels of hippocampal 5-HT(1A) receptor mRNA both in wild-type as in heterozygous knockout mice. These increases were paralleled by small but statistically significant changes in [3H]8-OH-DPAT binding. These results support a suppressive control of B over 5-HT(1A) receptor expression in the hippocampus of the mouse, which is predominantly mediated via the mineralocorticoid receptor. The data indicates that no interaction between the two corticosteroid receptors is required for this effect of corticosterone, and that mineralocorticoid receptor-mediated suppression of gene expression can take place in the complete absence of glucocorticoid receptor.

Adrenalectomy↗
PubMed1997

Elevated basal trough levels of corticosterone suppress hippocampal 5-hydroxytryptamine(1A) receptor expression in adrenally intact rats: implication for the pathogenesis of depression.

Several studies with adrenalectomized rats have shown that the suppressive effects of exogenous corticosteroids on 5-hydroxytryptamine(1A) receptor function are mediated by the high-affinity mineralocorticoid receptor, rather than the lower affinity glucocorticoid receptor. In the present study, adrenally intact rats were subcutaneously implanted for six days with pellets containing a small amount of corticosterone, which leads to a flattening of the circadian rhythm in the level of circulating hormone. The peak in daily corticosterone is suppressed, the basal trough is increased, and the hormone levels remain at a constant value equivalent to the daily average of about 5 microg/dl, which is usually observed in rats. Accordingly, this regime of corticosterone treatment did not enhance exclusively glucocorticoid receptor-controlled parameters, such as the weight of the thymus. Effects involving mineralocorticoid receptor activation were enhanced, since reductions were observed in stress-induced plasma corticosterone levels and adrenal weight. 5-Hydroxytryptamine(1A) receptor messenger RNA levels were found to be suppressed by approximately 25% in the dentate gyrus of the hippocampus of these corticosterone pellet-implanted rats. This suppression was reflected in significantly reduced [3H]8-hydroxy-2-(di-n-propylamino)tetralin binding in the hippocampal region. We propose therefore that this suppressive effect on 5-hydroxytryptamine(1A) receptor expression involves enhanced occupation of mineralocorticoid receptors, under a condition of elevated basal trough corticosteroid levels as is commonly observed in human depression.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Enhanced 5-HT1A receptor expression in forebrain regions of aggressive house mice.

The brain 5-HT1A receptor system in male wild house mice selected for high and low offensive aggression was investigated by autoradiographic analysis of in situ hybridization and radioligand binding. In high-aggressive mice, characterized by a short attack latency, the rise in plasma corticosterone concentration during the early dark phase was reduced. At that time the level of 5-HT1A mRNA in the dorsal hippocampus (dentate gyrus and CA1) was twice the amount measured in low-aggressive mice that had long attack latency and high plasma corticosterone level. Increased postsynaptic 5-HT1A receptor radioligand binding was found in dentate gyrus, CA1, lateral septum, and frontal cortex. No difference in ligand binding was found for the 5-HT1A autoreceptor on cell bodies in the dorsal raphe nucleus. In conclusion, genetic selection for high offensive aggression co-selects for reduced (circadian peak) level in plasma corticosterone and increased postsynaptic 5-HT1A receptor number in limbic and cortical regions.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Molecular dissection of corticosteroid action in the rat hippocampus. Application of the differential display techniques.

Both adrenal steroids and glutamate are crucial for hippocampal cell viability. In order to identify adrenal steroid- and glutamate-responsive genes controlling hippocampal cell viability, we have used the PCR-based differential display method. We have described the characteristics of this technique and how it can be automated. Using differential display, we have identified a number of rat hippocampal genes of which the expression is affected by a combination of the glutamate analog kainic acid and adrenalectomy. Administration of kainic acid or removal of the adrenals alone gave a limited number of differentially displayed genes. Therefore, our results indicate that the main mode of corticosteroid receptor-controlled gene expression in the hippocampus is interaction with other transcription factors (e.g., CREB, AP-1) and not by binding to hormone-responsive elements of corticosterone-specific genes. Characterization by multiplex PCR experiments of a differentially displayed fragment of which the expression is increased by the combination of kainic acid and adrenalectomy confirmed our differential display results. Further characterization by DNA sequence analysis of the corresponding full-length cDNA clone revealed a gene product with 91.4% sequence identity with the mouse transcription factor KROX-20, suggesting that we have cloned the rat homolog. This finding suggests a role of KROX-20 in corticosteroid- and kainic acid-controlled hippocampal plasticity.

Adrenalectomy↗
PubMed1995

A role for the mineralocorticoid receptor in a rapid and transient suppression of hippocampal 5-HT1A receptor mRNA by corticosterone.

The interaction between corticosterone and hippocampal 5-HT1A receptor mRNA expression was investigated in male rats. Two days after adrenalectomy, 5-HT1A receptor mRNA was increased in the granule cell layer of the dentate gyrus. Injection of corticosterone led to a significant dose-dependent and transient suppression of 5-HT1A receptor mRNA. The effect of a low dose of corticosterone (50 micrograms/kg) could be blocked by RU 28318, a specific mineralocorticoid receptor antagonist, but not by RU 38486, a glucocorticoid antagonist. The effect of a higher dose of corticosterone (300 micrograms/kg) could be partially blocked by RU 28318, whereas there was no additional effect of RU 38486. These results point to a stringent regulation of hippocampal 5-HT1A receptors by corticosterone that is predominantly mediated by the mineralocorticoid receptor.

Adrenalectomy↗
PubMed1994

Corticosterone suppresses the expression of 5-HT1A receptor mRNA in rat dentate gyrus.

The effect of corticosterone on 5-HT1A receptor mRNA expression in different hippocampal cell fields was studied by in situ hybridisation. One week after adrenalectomy or chronic corticosterone treatment, the 5-HT1A receptor mRNA showed a negative, but not linear, correlation with plasma corticosterone levels over a wide concentration range, specifically in the dentate gyrus. The data suggest an involvement of the mineralocorticoid receptor in the regulation of the 5-HT1A receptor mRNA and a possible synergistic effect of additional glucocorticoid receptor activation.

Adrenalectomy↗