Regulation of the rat serotonin-1A receptor gene by corticosteroids.
Dysregulation of the serotonergic system and abnormalities of the hypothalamic-pituitary-adrenal axis function have been implicated to be involved in neuropsychiatric disorders. Serotonin-1A receptors have been shown to be suppressed by corticosteroid hormones in a variety of animal studies. This effect may play a central role in the pathophysiology of depression. However, little is known about the molecular mechanism underlying this suppressive effect of corticosteroids. Here, we show by functional analysis of the promoter region of the rat serotonin-1A receptor gene that two NF-kappaB elements in the promoter contribute to induced transcription of the rat serotonin-1A receptor gene. Furthermore, we show that corticosteroids repress this NF-kappaB-mediated induction of transcription. Remarkably, we observed that only the glucocorticoid receptor and not the mineralocorticoid receptor was able to mediate this repressive effect of corticosteroids. We argue that negative cross-talk between the glucocorticoid receptor and NF-kappaB may provide a basis for the molecular mechanism underlying the negative action of corticosteroids on serotonin signaling in the brain.
Wissink
S
S
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
Meijer
O
O
Pearce
D
D
van Der Burg
B
B
van Der Saag
P T
PT
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006854:Hydrocortisone / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D011985:Receptors, Serotonin / Q000235:genetics*; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins / Q000096:biosynthesis; D017384:Sequence Deletion; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D000305:Adrenal Cortex Hormones; D016328:NF-kappa B; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins; D000450:Aldosterone; D003907:Dexamethasone; D006854:Hydrocortisone