Work

Correction: The Stimulatory Adenosine Receptor ADORA2B Regulates Serotonin (5-HT) Synthesis and Release in Oxygen-Depleted EC Cells in Inflammatory Bowel Disease

Year: 2013

Type: erratum

Abstract: Objective: We recently demonstrated that hypoxia, a key feature of IBD, increases enterochromaffin (EC) cell 5-HT secretion, which is also physiologically regulated by the ADORA2B mechanoreceptor.Since hypoxia is associated with increased extracellular adenosine, we wanted to examine whether this nucleotide amplifies HIF-1a-mediated 5-HT secretion.Design: The effects of hypoxia were studied on IBD mucosa, isolated IBD-EC cells, isolated normal EC cells and the EC cell tumor derived cell line KRJ-1.Hypoxia (0.5% O 2 ) was compared to NECA (adenosine agonist), MRS1754 (ADORA2B receptor antagonist) and SCH442146 (ADORA2A antagonist) on HIF signaling and 5-HT secretion.Antisense approaches were used to mechanistically evaluate EC cells in vitro.PCR and western blot were used to analyze transcript and protein levels of HIF-1a signaling and neuroendocrine cell function.An animal model of colitis was evaluated to confirm hypoxia:adenosine signaling in vivo.Results: HIF-1a is upregulated in IBD mucosa and IBD-EC cells, the majority (,90%) of which express an activated phenotype in situ.Hypoxia stimulated 5-HT release maximally at 30 mins, an effect amplified by NECA and selectively inhibited by MRS1754, through phosphorylation of TPH-1 and activation of VMAT-1.Transient transfection with Renilla luciferase under hypoxia transcriptional response element (HRE) control identified that ADORA2B activated HIF-1a signaling under hypoxic conditions.Additional signaling pathways associated with hypoxia:adenosine included MAP kinase and CREB.Antisense approaches mechanistically confirmed that ADORA2B signaling was linked to these pathways and 5-HT release under hypoxic conditions.Hypoxia:adenosine activation which could be reversed by 59-ASA treatment was confirmed in a TNBS-model. Conclusion:Hypoxia induced 5-HT synthesis and secretion is amplified by ADORA2B signaling via MAPK/CREB and TPH-1 activation.Targeting ADORA2s may decrease EC cell 5-HT production and secretion in IBD.

Source: PLoS ONE

DOI: 10.1371/annotation/99ad70ea-d3ca-485c-a1b4-50c107941c94