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.