RNA editing of 5-HT_2CR impairs insulin secretion of pancreatic beta cells via altered store-operated calcium entry

Recent studies emphasize the importance of 5-HT2C receptor (5-HT_2CR) signaling in the regulation of energy homeostasis. The 5-HT_2CR 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-HT_2CR has emerged as an important role in the modulation of pancreatic β cell functions. This study investigated mechanisms behind the effects of palmitic acid (PA) on insulin secretion in different overexpressed 5-HT_2CR edited isoforms in pancreatic MIN6 β cells. Results showed that the expressions of 5HT_2CR 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-HT_2CR and ADAR2 in pancreatic MIN6 β cells. PA treatment significantly induced the editing of 5-HT_2CR in pancreatic MIN6 β cells. There was no significant difference in cell viability between naïve cells and three overexpressed 5-HT_2CR edited isoforms in pancreatic MIN6 β cells. Overexpressed 5-HT_2CR edited isoforms showed reduced glucose-stimulated insulin secretion (GSIS) compared with green fluorescent protein (GFP) expressed cells. Moreover, 5-HT_2CR 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-HT_2CR modulates GSIS through alteration of ER calcium release and SOCE activation in pancreatic MIN6 β cells.