Glucagon-like peptide-1 analogue exendin-4 modulates serotonin transporter expression in intestinal epithelial cells

Serotonin-selective reuptake transporter (SERT) regulates extracellular availability of serotonin (5-hydroxytryptamine; 5-HT) and participates in the pathogenesis of functional disorders. Colonic SERT expression is decreased in colonic sensitized rats, and the glucagon-like peptide-1 analogue, exendin-4, reduces visceral hypersensitivity by decreasing 5-HT levels and increasing SERT expression. The present in vitro study aimed to further investigate the effects of exendin-4 on SERT expression, and to examine the role of GLP-1 and its receptor in the regulation of 5-HT. SERT mRNA and protein expression levels were detected by reverse transcription-quantitative PCR and western blotting. A ([3H]−)5-HT reuptake experiment was performed in IEC-6 rat intestinal epithelial cells treated with exendin-4. Effects on the adenosine cyclophosphate (AC)/PKA pathway were examined by variously treating cells with the AC activator forskolin, the protein kinase A (PKA) inhibitor H89 and the AC inhibitor SQ22536. Exendin-4 treatment upregulated SERT expression and enhanced 5-HT reuptake in IEC-6 cells. Also, PKA activity in IEC-6 cells was increased by both exendin-4 and forskolin, whereas these effects were abolished by the pre-treatment of exendin-9, which is a GLP-1R inhibitor, SQ22536 and H89. In conclusion, exendin-4 may be associated with the upregulation of SERT expression via the AC/PKA signaling pathway.