title: Regulation of type 1 IP₃ receptor expression by dopamine D2-like receptors via AP-1 and NFATc4 activation.
abstract: Type 1 inositol 1,4,5-trisphosphate receptors (IP₃Rs-1), together with ryanodine receptors, are major calcium channels to regulate intracellular Ca²⁺ concentration. Although our recent report demonstrates the essential involvement of IP₃R-1 up-regulation induced by dopamine D1-like and D2-like receptor (D1 and D2R) stimulation in psychological dependence, exact regulatory mechanisms of IP₃R-1 expression by D2Rs have not yet been clarified. Mouse cerebral cortical neurons were treated with inhibitor of Ca²⁺-related signal transduction pathways coupling to D2Rs and used to analyze the mechanisms of IP₃R-1 expression regulated by transcriptional factor. A selective D2R agonist, quinpirole, up-regulated IP₃R-1 protein following its mRNA increase, which was significantly inhibited by gallein (a Gβγ modulator), U73122 (a phospholipase C inhibitor), BAPTA-AM (an intracellular calcium chelating reagent), W7 (a calmodulin inhibitor), KN-93 (a calmodulin-dependent protein kinases inhibitor), and FK506 (a calcineurin inhibitor). Immunocytochemical assessment showed that quinpirole increased expression of both cFos and phosphorylated-cJun in nucleus and enhanced translocation of NFATc4 complex to nucleus from cytoplasm. In addition, quinpirole directly recruited bindings between AP-1 and IP₃R-1 promoter region and between NFATc4 and IP₃R-1 promoter region. These results indicate that D2Rs enhance IP₃R-1 gene transcription via increased bindings of AP-1 and NFATc4 to IP₃R-1 promoter region after Gβγ activation.
authors.affiliation: Department of Pharmacology, Kawasaki Medical School, Matsushima 577, Kurashiki 701-0192, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Mizuno
authors.forename: K
authors.initials: K
authors.lastname: Kurokawa
authors.forename: S
authors.initials: S
authors.lastname: Ohkuma
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D019257:Quinpirole / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; C025389:Itpr1 protein, mouse; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C467907:Nfatc4 protein, mouse; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D018808:Transcription Factor AP-1; D019257:Quinpirole