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SHR Neuro Cancer Cardio Lipid Metab Microb

Dammen, R; Damen, R; Haugen, M; Svejda, B; Alaimo, D; Brenna, O; Pfragner, R; Gustafsson, BI; Kidd, M.
The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease.
PLoS One. 2013; 8(4):e62607-e62607 Doi: 10.1371/journal.pone.0062607 [OPEN ACCESS]
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Co-authors Med Uni Graz: Pfragner Roswitha
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Abstract:: 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-1α-mediated 5-HT secretion. 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% O2) 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-1α signaling and neuroendocrine cell function. An animal model of colitis was evaluated to confirm hypoxia:adenosine signaling in vivo. HIF-1α 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-1α 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 5'-ASA treatment was confirmed in a TNBS-model. 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.
Find related publications in this database (using NLM MeSH Indexing): Adenosine - pharmacology; Adult -; Aged -; Animals -; Cell Hypoxia - drug effects; Colitis - metabolism; Disease Models, Animal -; Enterochromaffin Cells - drug effects; Female -; Humans -; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Inflammatory Bowel Diseases - metabolism; Intestinal Mucosa - drug effects; Male -; Middle Aged -; Oxygen - pharmacology; RNA, Messenger - genetics; Rats -; Rats, Sprague-Dawley -; Receptor, Adenosine A2B - metabolism; Response Elements - genetics; Serotonin - biosynthesis; Signal Transduction - drug effects; Trinitrobenzenesulfonic Acid -