title: Nurr1 expression is regulated by voltage-dependent calcium channels and calcineurin in cultured hippocampal neurons.
abstract: Nurr1 is an orphan nuclear transcription factor expressed in the brain. While Nurr1 is assumed to be an immediate early gene, it is not fully understood how Nurr1 expression is regulated in an activity-dependent manner in the central nervous system. Here, we investigated the molecular mechanisms underlying the regulation of Nurr1 expression in cultured hippocampal and cortical neurons. We found that upregulation of neural activity by high KCl and bicuculline enhances Nurr1 levels, while blockade of its activity by tetrodotoxin reduces Nurr1 levels. The induction of Nurr1 expression was mediated by voltage-dependent calcium channels (VDCCs), as shown by cadmium and VDCC-specific inhibitors. Furthermore, calcineurin, but not calcium/calmodulin-dependent protein kinase (CaMK) was critical for the induction. Thus, Nurr1 expression is regulated by VDCC and calcineurin in a cell-autonomous, neural activity-dependent manner.
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tokuoka
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hatanaka
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch F-67400, France; CNRS UMR7104, Illkirch, France; INSERM U964, Illkirch, France; Université de Strasbourg, Strasbourg, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan. Electronic address: hichinos@bio.titech.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichinose
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D015220:Calcium Channels / Q000502:physiology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000096:biosynthesis*; D016559:Tacrolimus / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D015220:Calcium Channels; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D013779:Tetrodotoxin; D019703:Calcineurin; D016559:Tacrolimus
keywords: 6-Cyano-7-nitroquinoxaline-2,3-dione; CNQX; CaMK; Calcineurin; DL-2-Amino-5-phosphonopentanoic acid; DL-APV; Hippocampal neurons; Nurr1 (Nr4a2); TTX; Transcription; VDCC; Voltage-dependent calcium channel; calcium/calmodulin-dependent protein kinase; tetrodotoxin; voltage-dependent calcium channel