The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease.

<h4>Objective</h4>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 exa...

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Autores principales:	Rikard Dammen, Martin Haugen, Bernhard Svejda, Daniele Alaimo, Oystein Brenna, Roswitha Pfragner, Bjorn I Gustafsson, Mark Kidd
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/de0dda719cba4e43970fabcdcbfedceb
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spelling	oai:doaj.org-article:de0dda719cba4e43970fabcdcbfedceb2021-11-18T07:47:43ZThe stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease.1932-620310.1371/journal.pone.0062607https://doaj.org/article/de0dda719cba4e43970fabcdcbfedceb2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23638125/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Objective</h4>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.<h4>Design</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.Rikard DammenMartin HaugenBernhard SvejdaDaniele AlaimoOystein BrennaRoswitha PfragnerBjorn I GustafssonMark KiddPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e62607 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rikard Dammen Martin Haugen Bernhard Svejda Daniele Alaimo Oystein Brenna Roswitha Pfragner Bjorn I Gustafsson Mark Kidd The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease.
description	<h4>Objective</h4>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.<h4>Design</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.
format	article
author	Rikard Dammen Martin Haugen Bernhard Svejda Daniele Alaimo Oystein Brenna Roswitha Pfragner Bjorn I Gustafsson Mark Kidd
author_facet	Rikard Dammen Martin Haugen Bernhard Svejda Daniele Alaimo Oystein Brenna Roswitha Pfragner Bjorn I Gustafsson Mark Kidd
author_sort	Rikard Dammen
title	The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease.
title_short	The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease.
title_full	The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease.
title_fullStr	The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease.
title_full_unstemmed	The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease.
title_sort	stimulatory adenosine receptor adora2b regulates serotonin (5-ht) synthesis and release in oxygen-depleted ec cells in inflammatory bowel disease.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/de0dda719cba4e43970fabcdcbfedceb
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The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease.

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