Differential promotion of glutamate transporter expression and function by glucocorticoids in astrocytes from various brain regions.
Steroids that activate glucocorticoid receptors (GRs) and mineralocorticoid receptors have important regulatory effects on neural development, plasticity, and the body's stress response. Here, we investigated the role of corticosteroids in regulating the expression of the glial glutamate transporters glial glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter (GLAST) in rat primary astrocytes. The synthetic glucocorticoid dexamethasone provoked a marked increase of GLT-1 transcription and protein levels in cortical astrocytes, whereas GLAST expression remained unaffected. Up-regulation of GLT-1 expression was accompanied by an enhanced glutamate uptake, which could be blocked by the specific GLT-1 inhibitor dihydrokainate. The promoting effect of dexamethasone on GLT-1 gene expression and function was abolished by the GR antagonist mifepristone. A predominant role of the GR was further supported by the observation that corticosterone could elevate GLT-1 expression in a dose-dependent manner, whereas aldosterone, the physiological ligand of the mineralocorticoid receptor, exerted only weak effects even when applied at high concentrations. Moreover, we monitored brain region-specific differences, since all corticosteroids used in this study failed to alter the expression of GLT-1 in midbrain and cerebellar glia, although expression levels of both corticosteroid receptor subtypes were similar in all brain regions analyzed. Dexamethasone, however, modestly enhanced GLT-1 expression in cerebellar glia in combination with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine, suggesting that suppression of GLT-1 expression in cerebellar cultures may at least in part be epigenetically mediated by a DNA methylation-dependent process. Taken together, our data highlight a potential role for glucocorticoids in regulating GLT-1 gene expression during central nervous system development or pathophysiological processes including stress.
Zschocke
Jürgen
J
Department of Pathobiochemistry, Johannes Gutenberg University Mainz, 55099 Mainz, Germany.
Bayatti
Nadhim
N
Clement
Albrecht M
AM
Witan
Heidrun
H
Figiel
Maciej
M
Engele
Jürgen
J
Behl
Christian
C
D000305:Adrenal Cortex Hormones / Q000378:metabolism; D027322:Amino Acid Transport System X-AG / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002490:Central Nervous System / Q000473:pathology; D002531:Cerebellum / Q000473:pathology; D003345:Corticosterone / Q000378:metabolism / Q000494:pharmacology; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D000077209:Decitabine; D003902:Detergents / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes / Q000494:pharmacology; D005938:Glucocorticoids / Q000737:chemistry*; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology; D009457:Neuroglia / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
D000305:Adrenal Cortex Hormones; D027322:Amino Acid Transport System X-AG; D017931:DNA Primers; D003902:Detergents; D005456:Fluorescent Dyes; D005938:Glucocorticoids; D008024:Ligands; D018161:Receptors, Mineralocorticoid; D015735:Mifepristone; C020889:dihydrokainic acid; D000077209:Decitabine; D003907:Dexamethasone; D008156:Luciferases; D015254:DNA Modification Methylases; D001374:Azacitidine; D007608:Kainic Acid; D003345:Corticosterone