title: Translational control of nociception via 4E-binding protein 1.
abstract: Activation of the mechanistic/mammalian target of rapamycin (mTOR) kinase in models of acute and chronic pain is strongly implicated in mediating enhanced translation and hyperalgesia. However, the molecular mechanisms by which mTOR regulates nociception remain unclear. Here we show that deletion of the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a major mTOR downstream effector, which represses eIF4E activity and cap-dependent translation, leads to mechanical, but not thermal pain hypersensitivity. Mice lacking 4E-BP1 exhibit enhanced spinal cord expression of neuroligin 1, a cell-adhesion postsynaptic protein regulating excitatory synapse function, and show increased excitatory synaptic input into spinal neurons, and a lowered threshold for induction of synaptic potentiation. Pharmacological inhibition of eIF4E or genetic reduction of neuroligin 1 levels normalizes the increased excitatory synaptic activity and reverses mechanical hypersensitivity. Thus, translational control by 4E-BP1 downstream of mTOR effects the expression of neuroligin 1 and excitatory synaptic transmission in the spinal cord, and thereby contributes to enhanced mechanical nociception.
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Canada.|Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Canada.
authors.forename: Arkady
authors.initials: A
authors.lastname: Khoutorsky
authors.affiliation: Unité de neurosciences cellulaires et moléculaire, Institut universitaire en santé mentale de Québec, Québec, Canada.
authors.forename: Robert P
authors.identifier: http://orcid.org/0000-0002-3287-6803
authors.initials: RP
authors.lastname: Bonin
authors.affiliation: Department of Psychology, McGill University, Montréal, Canada.|Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sorge
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Canada.|Centre for Integrative Physiology and The Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Christos G
authors.initials: CG
authors.lastname: Gkogkas
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: Sophie Anne
authors.initials: SA
authors.lastname: Pawlowski
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Canada.|Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Canada.
authors.forename: Seyed Mehdi
authors.initials: SM
authors.lastname: Jafarnejad
authors.affiliation: National Center for Complementary and Alternative Medicine, National Institutes of Health, Porter Neuroscience Research Center, Maryland, United States.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Pitcher
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Canada.|Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Canada.
authors.forename: Tommy
authors.initials: T
authors.lastname: Alain
authors.affiliation: Unité de neurosciences cellulaires et moléculaire, Institut universitaire en santé mentale de Québec, Québec, Canada.
authors.forename: Jimena
authors.initials: J
authors.lastname: Perez-Sanchez
authors.affiliation: Unité de neurosciences cellulaires et moléculaire, Institut universitaire en santé mentale de Québec, Québec, Canada.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Salter
authors.affiliation: Department of Psychology, McGill University, Montréal, Canada.|Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada.
authors.forename: Loren
authors.initials: L
authors.lastname: Martin
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ribeiro-da-Silva
authors.affiliation: Unité de neurosciences cellulaires et moléculaire, Institut universitaire en santé mentale de Québec, Québec, Canada.|Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.|Department of Psychiatry and Neuroscience, Université Laval, Québec, Canada.
authors.forename: Yves
authors.identifier: http://orcid.org/0000-0002-5779-9330
authors.initials: Y
authors.lastname: De Koninck
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada.|Anesthesia Research Unit, McGill University, Montreal, Canada.
authors.forename: Fernando
authors.initials: F
authors.lastname: Cervero
authors.affiliation: Department of Psychology, McGill University, Montréal, Canada.|Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Canada.|Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Canada.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D018797:Cell Cycle Proteins; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051379:Mice; D059225:Nociception; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; C000601282:eIF4E protein, mouse; C093438:neuroligin 1
keywords: biochemistry; eIF4F complex; mRNA translation; mouse; neuroscience; pain