title: Mechanism of ER stress-induced brain damage by IP(3) receptor.
abstract: Deranged Ca(2+) signaling and an accumulation of aberrant proteins cause endoplasmic reticulum (ER) stress, which is a hallmark of cell death implicated in many neurodegenerative diseases. However, the underlying mechanisms are elusive. Here, we report that dysfunction of an ER-resident Ca(2+) channel, inositol 1,4,5-trisphosphate receptor (IP(3)R), promotes cell death during ER stress. Heterozygous knockout of brain-dominant type1 IP(3)R (IP(3)R1) resulted in neuronal vulnerability to ER stress in vivo, and IP(3)R1 knockdown enhanced ER stress-induced apoptosis via mitochondria in cultured cells. The IP(3)R1 tetrameric assembly was positively regulated by the ER chaperone GRP78 in an energy-dependent manner. ER stress induced IP(3)R1 dysfunction through an impaired IP(3)R1-GRP78 interaction, which has also been observed in the brain of Huntington's disease model mice. These results suggest that IP(3)R1 senses ER stress through GRP78 to alter the Ca(2+) signal to promote neuronal cell death implicated in neurodegenerative diseases.
authors.affiliation: Department of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Takayasu
authors.initials: T
authors.lastname: Higo
authors.forename: Kozo
authors.initials: K
authors.lastname: Hamada
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hisatsune
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hashikawa
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Hattori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004734:Energy Metabolism / Q000502:physiology; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018832:Molecular Chaperones; D002118:Calcium