Abstract
Serotonin (5-HT) is a monoamine neurotransmitter and plays important roles in several of the human body’s systems. Known as a primary target for psychoactive drug development, the 5-HT transporter (5-HTT, SERT) plays a critical role in the regulation of serotonergic function by reuptaking 5-HT. The allelic variation of 5-HTT expression is caused by functional gene promoter polymorphism with two principal variant alleles, 5-HTT gene-linked polymorphic region (5-HTTLPR). It has been demonstrated that 5-HTTLPR is associated with numerous neuropsychiatric disorders. The functional roles of 5-HTTLPR have been reported in human choriocarcinoma (JAR), lymphoblast and raphe cells. To date, the significance of 5-HTTLPR in gastrointestinal tract-derived cells has never been elucidated. Thus, the impact of 5-HTTLPR on 5-HTT transcription was studied in SW480 human colon carcinoma cells, which were shown to express 5-HTT. We found 42-bp fragment in long (L) allele as compared to short (S) allele, and this allelic difference resulted in 2-fold higher transcriptional efficiency of L allele (P < 0.05) as demonstrated using a functional reporter gene assay. Nevertheless, the transcriptional effect of estrogen and glucocorticoid on 5-HTT expression via 5-HTTLPR was not found in this cell line. Our study was the first to demonstrate the molecular role of this allelic variation in gastrointestinal tract cells.
Highlights
Serotonin (5-Hydroxytryptamine, 5-HT) is most frequently thought of as a monoamine neurotransmitter in the central nervous system (CNS)
polymerase chain reaction (PCR) amplification products were generated with primers flanking the 5-HTTLPR using different genomic DNA templates and analyzed by DNA sequencing
We discovered a differential regulation of 5-HTT expression by 5-HTTLPR in human cell line derived from the GI tract
Summary
Serotonin (5-Hydroxytryptamine, 5-HT) is most frequently thought of as a monoamine neurotransmitter in the central nervous system (CNS). Mucosal 5-HT molecules have to be very rapidly metabolized, mainly as a result of the activity of monoamine oxidase by an inactivating mechanism, a transporter-mediated uptake, in the gut because circulating free 5-HT is toxic and passive diffusion is too slow to prevent the accumulation of 5-HT in contact with its receptors [8] This process is mediated by the similar transporter utilized by serotonergic neurons, known as the 5-HT transporter (5-HTT or SERT) which is present both in the mucosa and in nerves of the enteric nervous system (ENS). Prior to reporter gene assays, we examined whether mRNA transcripts for 5-HTT, glucocorticoid receptor (GR) and estrogen receptor (ER) are expressed in human colon carcinoma cell lines, SW480 and HT-29, using the reverse transcription-polymerase chain reaction (RT-PCR) method for evaluating an appropriate cell model
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