title: The A2A adenosine receptor is a dual coding gene: a novel mechanism of gene usage and signal transduction.
abstract: The A2A adenosine receptor (A2AR) is a G protein-coupled receptor and a major target of caffeine. The A2AR gene encodes alternative transcripts that are initiated from at least two independent promoters. The different transcripts of the A2AR gene contain the same coding region and 3'-untranslated region and different 5'-untranslated regions that are highly conserved among species. We report here that in addition to the production of the A2AR protein, translation from an upstream, out-of-frame AUG of the rat A2AR gene produces a 134-amino acid protein (designated uORF5). An anti-uORF5 antibody recognized a protein of the predicted size of uORF5 in PC12 cells and rat brains. Up-regulation of A2AR transcripts by hypoxia led to increased levels of both the A2AR and uORF5 proteins. Moreover, stimulation of A2AR increased the level of the uORF5 protein via post-transcriptional regulation. Expression of the uORF5 protein suppressed the AP1-mediated transcription promoted by nerve growth factor and modulated the expression of several proteins that were implicated in the MAPK pathway. Taken together, our results show that the rat A2AR gene encodes two distinct proteins (A2AR and uORF5) in an A2AR-dependent manner. Our study reveals a new example of the complexity of the mammalian genome and provides novel insights into the function of A2AR.
authors.affiliation: From the Institute of Neuroscience, School of Life Sciences, National Yang Ming University, Taipei 112, Taiwan.
authors.forename: Chien-fei
authors.initials: CF
authors.lastname: Lee
authors.forename: Hsin-Lin
authors.initials: HL
authors.lastname: Lai
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Lee
authors.forename: Chen-Li
authors.initials: CL
authors.lastname: Chien
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
mesh_terms: D020413:3' Untranslated Regions / Q000502:physiology; D020121:5' Untranslated Regions / Q000502:physiology*; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D016366:Open Reading Frames / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D043705:Receptor, Adenosine A2A
keywords: A2A Adenosine Receptor; AP1 Transcription Factor; Adenosine Receptor; Alternative Reading Frame; Dual Coding Gene; Gene Regulation; Hypoxia; Overlapping Reading Frame; Protein Kinase A (PKA)