title: Deletion of Atf6α enhances kainate-induced neuronal death in mice.
abstract: Excessive amount of L-glutamate in the brain causes neuronal damage in various pathological conditions including epilepsy and stroke. We previously reported that the 150-kDa oxygen-regulated protein (ORP150), a molecular chaperone in the endoplasmic reticulum (ER), inhibited the L-glutamate-induced neuronal death, at least partly, by improving Ca(2+) homeostasis in the ER. In the present study, we analyzed the role of activating transcription factor 6α (ATF6α), an upstream transcriptional factor critical for the operation of the ER, using mouse intrahippocampal kainate (KA) injection model. Expression of Hspa5, which encodes the molecular chaperone 78 kDa glucose-regulated protein (GRP78), increased after KA injection in the wild type (WT) mice. Comparative analysis using WT and Atf6α(-/-) mice revealed that KA induced pronounced neuronal death in the CA3 region of Atf6α(-/-) mice. The enhanced neuronal death in Atf6α(-/-) mice was associated with reduced expression of molecular chaperones in the ER and significant induction of c-fos in the hippocampal neurons. Furthermore, an injection of dantrolene, an inhibitor of ryanodine receptor, partially rescued these effects in Atf6α(-/-) mice after KA injection. Our results suggest that ATF6α plays an important role in neuronal survival after KA-induced excitotoxicity through the regulation of Ca(2+) response and neuronal activity.
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Science, Kanazawa University, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Kezuka
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Science, Kanazawa University, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Tkarada-Iemata
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Science, Kanazawa University, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Department of Biophysics, Graduate School of Science, Kyoto University, Japan; CREST (Core Research for Evolutionary Science and Technology), JST (Japan Science and Technology Agency), Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Japan; CREST (Core Research for Evolutionary Science and Technology), JST (Japan Science and Technology Agency), Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Science, Kanazawa University, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kitao
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Science, Kanazawa University, Japan; CREST (Core Research for Evolutionary Science and Technology), JST (Japan Science and Technology Agency), Japan. Electronic address: osamuh3@staff.kanazawa-u.ac.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Hori
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D056654:CA3 Region, Hippocampal / Q000473:pathology; D020013:Calcium Signaling / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D003620:Dantrolene / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D018690:Excitatory Amino Acid Agonists; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D003620:Dantrolene; D007608:Kainic Acid
keywords: ATF6α; Ca(2+); Kainate; Neuronal death; UPR