Glucocorticoid‐regulated human serotonin transporter (5‐HTT) expression is modulated by the 5‐HTT gene‐promotor‐linked polymorphic region

• Published in: Journal of neurochemistry Vol. 86; no. 5; pp. 1072 - 1078
• Main Authors: Glatz, K., Mössner, R., Heils, A., Lesch, K. P.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-09-2003; Blackwell
• Subjects: anxiety; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; Binding, Competitive - drug effects; Biological and medical sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Cell physiology; Choriocarcinoma - metabolism; Cocaine - analogs & derivatives; Cocaine - pharmacokinetics; Dexamethasone - pharmacology; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - physiology; Genes, Reporter; glucocorticoid hormone; Glucocorticoids - metabolism; Humans; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Transport Proteins; Molecular and cellular biology; Nerve Tissue Proteins; Neurotransmission; Polymerase Chain Reaction; promoter; Promoter Regions, Genetic - physiology; serotonin; Serotonin Plasma Membrane Transport Proteins; serotonin transporter; stress; Transfection; Human; Serotoninergic transmission; Serotonin; Glucocorticoid; Uptake; Stress; Serotonin transporter; glucocorticoid hormone; Hormonal regulation; Neurotransmitter; Anxiety; promoter; Carrier protein; Polymorphism
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2003.01944.x

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.