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Physiol. Genomics 23: 89-102, 2005. First published July 26, 2005; doi:10.1152/physiolgenomics.00068.2005
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Genetic and pharmacological inactivation of adenosine A_2A receptor reveals an Egr-2-mediated transcriptional regulatory network in the mouse striatum

¹ Department of Neurology, Boston University School of Medicine, Boston; ² Bioinformatics Program and ³ Department of Biomedical Engineering, Boston University, Boston; and ⁴ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts

The adenosine A_2A receptor (A_2AR) is highly expressed in the striatum, where it modulates motor and emotional behaviors. We used both microarray and bioinformatics analyses to compare gene expression profiles by genetic and pharmacological inactivation of A_2AR and inferred an A_2AR-controlled transcription network in the mouse striatum. A comparison between vehicle (VEH)-treated A_2AR knockout (KO) mice (A_2AR KO-VEH) and wild-type (WT) mice (WT-VEH) revealed 36 upregulated genes that were partially mimicked by treatment with SCH-58261 (SCH; an A_2AR antagonist) and 54 downregulated genes that were not mimicked by SCH treatment. We validated the A_2AR as a specific drug target for SCH by comparing A_2AR KO-SCH and A_2AR KO-VEH groups. The unique downregulation effect of A_2AR KO was confirmed by comparing A_2AR KO-SCH with WT-SCH gene groups. The distinct striatal gene expression profiles induced by A_2AR KO and SCH should provide clues to the molecular mechanisms underlying the different phenotypes observed after genetic and pharmacological inactivation of A_2AR. Furthermore, bioinformatics analysis discovered that Egr-2 binding sites were statistically overrepresented in the proximal promoters of A_2AR KO-affected genes relative to the unaffected genes. This finding was further substantiated by the demonstration that the Egr-2 mRNA level increased in the striatum of both A_2AR KO and SCH-treated mice and that striatal Egr-2 binding activity in the promoters of two A_2AR KO-affected genes was enhanced in A_2AR KO mice as assayed by chromatin immunoprecipitation. Taken together, these results strongly support the existence of an Egr-2-directed transcriptional regulatory network controlled by striatal A_2ARs.

SCH-58261; microarray; A_2A receptor antagonist; A_2A receptor knockout; promotor analysis