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

Abstract

Serotonin-selective reuptake transporter (SerT) regulates extracellular availability of serotonin (5-hydroxy-tryptamine; 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.