Recent studies emphasize the importance of 5-HT2C receptor (5-HT2CR) signaling in the regulation of energy homeostasis. The 5-HT2CR is the only G-protein-coupled receptor known to undergo post-transcriptional adenosine to inosine (A-to-I) editing by adenosine deaminase acting on RNA (ADAR). 5-HT2CR has emerged as an important role in the modulation of pancreatic beta cell functions. This study investigated mechanisms behind the effects of palmitic acid (PA) on insulin secretion in different overexpressed 5-HT2CR edited isoforms in pancreatic MIN6 beta cells. Results showed that the expressions of 5HT(2C)R and ADAR2 were upregulated in the pancreatic islets of mice fed with high-fat diet (HFD) compared to control mice. PA treatment significantly induced the expressions of 5-HT2CR and ADAR2 in pancreatic MIN6 beta cells. PA treatment significantly induced the editing of 5-HT2CR in pancreatic MIN6 beta cells. There was no significant difference in cell viability between naive cells and three overexpressed 5-HT2CR edited isoforms in pancreatic MIN6 beta cells. Overexpressed 5-HT2CR edited isoforms showed reduced glucose-stimulated insulin secretion (GSIS) compared with green fluorescent protein (GFP) expressed cells. Moreover, 5-HT2CR edited isoforms displayed reduced endoplasmic reticulum (ER) calcium release and store-operated calcium entry (SOCE) activation, probably through inhibition of stromal interaction molecule 1 trafficking under PA treatment. Altogether, our results show that PA-mediated editing of 5-HT2CR modulates GSIS through alteration of ER calcium release and SOCE activation in pancreatic MIN6 beta cells.
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