Novel promoter and alternate transcription start site of the human serotonin reuptake transporter in intestinal mucosa

Selective serotonin-reuptake inhibitors are therapies for psychological and bowel disorders, but produce adverse effects in the non-targeted system. To determine whether human serotonin-selective reuptake transporter (SERT) transcripts in the intestine are different from the brain, rapid amplification of cDNA ends, primer extension and RT-PCR assays were used to evaluate SERT transcripts from each region. Potential SLC6A4 gene promoter constructs were evaluated with a secreted alkaline phosphatase reporter assay. A novel transcript of the human SLC6A4 gene was discovered that predominates in the intestine, and differs from previous transcripts in the 5′-untranslated region. The distinct transcriptional start site and alternate promoter suggest that gastrointestinal SERT can be differentially regulated from brain SERT, may explain why the polymorphism in the previously identified promoter is associated with affective disorders, but not associated with gastrointestinal dysfunction, and suggest the intriguing possibility of the development of site-specific therapeutics for SERT regulation in the treatment of multiple disorders.