title: Pharmacological brake-release of mRNA translation enhances cognitive memory.
abstract: Phosphorylation of the α-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2α kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2α. This collection of signaling pathways is termed the 'integrated stress response' (ISR). eIF2α phosphorylation diminishes protein synthesis, while allowing preferential translation of some mRNAs. Starting with a cell-based screen for inhibitors of PERK signaling, we identified a small molecule, named ISRIB, that potently (IC50 = 5 nM) reverses the effects of eIF2α phosphorylation. ISRIB reduces the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress. eIF2α phosphorylation is implicated in memory consolidation. Remarkably, ISRIB-treated mice display significant enhancement in spatial and fear-associated learning. Thus, memory consolidation is inherently limited by the ISR, and ISRIB releases this brake. As such, ISRIB promises to contribute to our understanding and treatment of cognitive disorders. DOI:http://dx.doi.org/10.7554/eLife.00498.001.
authors.affiliation: Department of Biochemistry and Biophysics , University of California, San Francisco , San Francisco , United States ; Howard Hughes Medical Institute, University of California, San Francisco , San Francisco , United States.
authors.forename: Carmela
authors.initials: C
authors.lastname: Sidrauski
authors.forename: Diego
authors.initials: D
authors.lastname: Acosta-Alvear
authors.forename: Arkady
authors.initials: A
authors.lastname: Khoutorsky
authors.forename: Punitha
authors.initials: P
authors.lastname: Vedantham
authors.forename: Brian R
authors.initials: BR
authors.lastname: Hearn
authors.forename: Han
authors.initials: H
authors.lastname: Li
authors.forename: Karine
authors.initials: K
authors.lastname: Gamache
authors.forename: Ciara M
authors.initials: CM
authors.lastname: Gallagher
authors.forename: Kenny K-H
authors.initials: KK
authors.lastname: Ang
authors.forename: Chris
authors.initials: C
authors.lastname: Wilson
authors.forename: Voytek
authors.initials: V
authors.lastname: Okreglak
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
authors.forename: Byron
authors.initials: B
authors.lastname: Hann
authors.forename: Karim
authors.initials: K
authors.lastname: Nader
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Peter
authors.initials: P
authors.lastname: Walter
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D003071:Cognition; D003514:Cyclohexylamines / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015977:Eukaryotic Initiation Factor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008568:Memory; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: C000599093:2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide; D000081:Acetamides; D003514:Cyclohexylamines; D015977:Eukaryotic Initiation Factor-1; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C026022:eukaryotic peptide initiation factor-1A
keywords: ATF4; Human; Mouse; Rat; eIF2; eIF2B; integrated stress response; memory consolidation; unfolded protein response