title: Sigma-1Rs are upregulated via PERK/eIF2α/ATF4 pathway and execute protective function in ER stress.
abstract: Sigma-1 receptors (Sig-1Rs) are the ER resident proteins. Sig-1Rs in the brain have been reported to be significantly reduced in patients with schizophrenia. The impediment of regulating Sig-1Rs expression levels increases the risk for schizophrenia. Thus elucidating the mechanism regulating Sig-1Rs expression might provide the strategy to prevent mental disorders. In this study, we have demonstrated that Sig-1Rs were transcriptionally upregulated by ATF4 in ER stress. Moreover, ATF4 directly bounds to the 5' flanking region of Sig-1R gene. The reporter activities using this region were enhanced in ER stress, or by ATF4 alone. The reporter activities with the pathogenic polymorphisms (GC-241-240TT, T-485A) were reduced. In addition, the processing of Caspase-4 was inhibited by Sig-1Rs. These results indicate that Sig-1Rs are transcriptionally upregulated via the PERK/eIF2α/ATF4 pathway and ameliolate cell death signaling. This study is the first report identifying the transcription factor regulating Sig-1Rs expression.
authors.affiliation: Psychiatry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. te_mitsu@yahoo.co.jp
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Mitsuda
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Omi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tanimukai
authors.forename: Yukako
authors.initials: Y
authors.lastname: Sakagami
authors.forename: Shinji
authors.initials: S
authors.lastname: Tagami
authors.forename: Masayasu
authors.initials: M
authors.lastname: Okochi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudo
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D053471:Caspases, Initiator / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D011401:Promoter Regions, Genetic; D017480:Receptors, sigma / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics*; D014158:Transcription, Genetic; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D051701:Activating Transcription Factor 4; D053471:Caspases, Initiator; D015852:Eukaryotic Initiation Factor-2; D017480:Receptors, sigma; D019892:eIF-2 Kinase; D000097605:Sigma-1 Receptor; C093516:CASP4 protein, human