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Expression and Regulation of Intestine Specific Serotonin Transporter (iSERT) Variant

SERT is critical for regulating extracellular availability of serotonin (5‐HT) and is a therapeutic target for the treatment for multiple disorders. A novel transcription start site and alternative promoter for SERT gene has recently been demonstrated in human intestine. Decrease in intestinal SERT and consequent high 5‐HT levels are implicated in the pathophysiology of inflammatory and diarrheal disorders. Thus, characterization of this novel transcript is warranted for gut‐specific SERT‐targeted therapies. Therefore, tissue distribution and regulation of intestine specific SERT (iSERT) was investigated. SERT primers spanning exon 1c of human SERT gene were utilized. Human iSERT variant was highly expressed in the small intestine and placenta (Ileum>jejunum>placenta>duodenum) with low expression in colon and brain. Similarly, expression of iSERT mRNA was very low in colonic cell lines HT‐29, LS174T, SK015, T84 as compared to Caco‐2 (representing ileal phenotype upon differentiation). iSERT mRNA expression was not induced during Caco‐2 cells differentiation. iSERT promoter (upstream of exon 2) has potential binding sites for HNF3α. To understand the regulatory mechanisms of this novel transcript, its modulation by hepatocyte nuclear factors (HNFs) was investigated. siRNA mediated knock down of HNF3α suppressed iSERT mRNA levels in Caco‐2 cells. Over‐expression of HNF4α (but not HNF1α or HNF1β) by Amaxa transfection increased iSERT mRNA levels (~30 fold, p<0.05) as compared to empty vector. These studies demonstrate that HNF3α and HN4α upregulate intestine specific SERT gene expression that may underlie anti‐diarrheal or anti‐inflammatory effects of HNFs. Supported by NIH & VA.