1. Glucocorticoid-regulated human serotonin transporter (5-HTT) expression is modulated by the 5-HTT gene-promotor-linked polymorphic region.
- Author
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Glatz K, Mössner R, Heils A, and Lesch KP
- Subjects
- B-Lymphocytes drug effects, B-Lymphocytes metabolism, Binding, Competitive drug effects, Cell Line, Choriocarcinoma metabolism, Cocaine pharmacokinetics, Dexamethasone pharmacology, Dose-Response Relationship, Drug, Genes, Reporter, Humans, Polymerase Chain Reaction, Serotonin Plasma Membrane Transport Proteins, Transfection, Carrier Proteins genetics, Carrier Proteins metabolism, Cocaine analogs & derivatives, Gene Expression Regulation physiology, Glucocorticoids metabolism, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism, Membrane Transport Proteins, Nerve Tissue Proteins, Promoter Regions, Genetic physiology
- Abstract
Mood, emotion and cognition are modulated by serotonergic neurotransmission, while the physiological function of serotonergic synapses depends on serotonin reuptake, which is mediated by the serotonin transporter (5-HTT). Allelic variation of 5-HTT expression in humans is caused by a functional gene-promoter polymorphism with two predominant variant alleles, which are associated with variations in anxiety measures as previously reported. Here we report that administration of dexamethasone, a potent glucocorticosteroid hormone, results in an increase in 5-HTT expression in immortalized human B-lymphoblastoid cells, which express the human 5-HTT. Functional reporter gene assays as well as 5-HT uptake and inhibitor binding measures revealed a genotype-dependent dose-response to glucocorticosteroid administration, which was antagonized by RU 38486, a non-specific glucocorticosteroid hormone antagonist. The allele-specific differences after administration of dexamethasone depended on the repetitive GC-rich sequence located approximately 1.4 kb upstream of the 5-HTT gene transcription site because of absence of a significant steroid effect after transfecting a deletional mutant reporter gene construct, which lacks this repetitive promoter sequence. Our findings may contribute to explain the vulnerability to stress-related disorders in susceptible individuals, in whom further clinical studies should follow up on these in vitro findings.
- Published
- 2003
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