title: Chronic hypoxia upregulates adenosine 2a receptor expression in chromaffin cells via hypoxia inducible factor-2α: role in modulating secretion.
abstract: Catecholamine (CAT) release from chromaffin tissue plays an essential role in the fetus which develops in a low O₂ environment (hypoxia). To address molecular mechanisms regulating CAT secretion in low O₂, we exposed a fetal chromaffin-derived cell line (MAH cells) to chronic hypoxia (CHox; 2% O₂, 24h) and assessed gene expression using microarrays, quantitative RT-PCR, and western blot. CHox caused a dramatic ∼12× upregulation of adenosine A2a receptor (A2aR) mRNA, an effect critically dependent upon hypoxia-inducible factor (HIF)-2α which bound the promoter of the A2aR gene. In amperometric studies, acute hypoxia and high K⁺ (30 mM) evoked quantal CAT secretion that was enhanced after CHox, and further potentiated during simultaneous A2aR activation by adenosine. A2aR activation also enhanced stimulus-induced rise in intracellular Ca²⁺ in control, but not HIF-2α-deficient, MAH cells. Thus, A2aR, adenosine, and HIF-2α are key contributors to the potentiation of CAT secretion in developing chromaffin cells during chronic hypoxia.
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Brown
authors.forename: Edison P
authors.initials: EP
authors.lastname: Reyes
authors.forename: Colin A
authors.initials: CA
authors.lastname: Nurse
mesh_terms: D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D002460:Cell Line; D019439:Chromaffin Cells / Q000378:metabolism*; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D043704:Receptor, Adenosine A2B / Q000235:genetics*; D020218:Response Elements; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002118:Calcium; D002395:Catecholamines; D043704:Receptor, Adenosine A2B; D000099162:Endothelial PAS Domain-Containing Protein 1