PMID- 26678009
OWN - NLM
STAT- MEDLINE
DCOM- 20160822
LR  - 20201209
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 4
DP  - 2015 Dec 18
TI  - Translational control of nociception via 4E-binding protein 1.
LID - e12002 [pii]
LID - 10.7554/eLife.12002 [doi]
AB  - 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.
FAU - Khoutorsky, Arkady
AU  - Khoutorsky A
AD  - Department of Biochemistry, McGill University, Montreal, Canada.
AD  - Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, 
      Canada.
FAU - Bonin, Robert P
AU  - Bonin RP
AUID- ORCID: 0000-0002-3287-6803
AD  - Unite de neurosciences cellulaires et moleculaire, Institut universitaire en 
      sante mentale de Quebec, Quebec, Canada.
FAU - Sorge, Robert E
AU  - Sorge RE
AD  - Department of Psychology, McGill University, Montreal, Canada.
AD  - Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
FAU - Gkogkas, Christos G
AU  - Gkogkas CG
AD  - Department of Biochemistry, McGill University, Montreal, Canada.
AD  - Centre for Integrative Physiology and The Patrick Wild Centre, University of 
      Edinburgh, Edinburgh, United Kingdom.
FAU - Pawlowski, Sophie Anne
AU  - Pawlowski SA
AD  - Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
AD  - Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
FAU - Jafarnejad, Seyed Mehdi
AU  - Jafarnejad SM
AD  - Department of Biochemistry, McGill University, Montreal, Canada.
AD  - Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, 
      Canada.
FAU - Pitcher, Mark H
AU  - Pitcher MH
AD  - National Center for Complementary and Alternative Medicine, National Institutes 
      of Health, Porter Neuroscience Research Center, Maryland, United States.
FAU - Alain, Tommy
AU  - Alain T
AD  - Department of Biochemistry, McGill University, Montreal, Canada.
AD  - Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, 
      Canada.
FAU - Perez-Sanchez, Jimena
AU  - Perez-Sanchez J
AD  - Unite de neurosciences cellulaires et moleculaire, Institut universitaire en 
      sante mentale de Quebec, Quebec, Canada.
FAU - Salter, Eric W
AU  - Salter EW
AD  - Unite de neurosciences cellulaires et moleculaire, Institut universitaire en 
      sante mentale de Quebec, Quebec, Canada.
FAU - Martin, Loren
AU  - Martin L
AD  - Department of Psychology, McGill University, Montreal, Canada.
AD  - Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
FAU - Ribeiro-da-Silva, Alfredo
AU  - Ribeiro-da-Silva A
AD  - Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
AD  - Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
FAU - De Koninck, Yves
AU  - De Koninck Y
AUID- ORCID: 0000-0002-5779-9330
AD  - Unite de neurosciences cellulaires et moleculaire, Institut universitaire en 
      sante mentale de Quebec, Quebec, Canada.
AD  - Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
AD  - Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
AD  - Department of Psychiatry and Neuroscience, Universite Laval, Quebec, Canada.
FAU - Cervero, Fernando
AU  - Cervero F
AD  - Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
AD  - Anesthesia Research Unit, McGill University, Montreal, Canada.
FAU - Mogil, Jeffrey S
AU  - Mogil JS
AD  - Department of Psychology, McGill University, Montreal, Canada.
AD  - Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
FAU - Sonenberg, Nahum
AU  - Sonenberg N
AD  - Department of Biochemistry, McGill University, Montreal, Canada.
AD  - Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, 
      Canada.
LA  - eng
GR  - MOP-114994/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151218
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Adhesion Molecules, Neuronal)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Eif4ebp1 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Phosphoproteins)
RN  - 0 (eIF4E protein, mouse)
RN  - 0 (neuroligin 1)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Carrier Proteins/genetics/*metabolism
MH  - Cell Adhesion Molecules, Neuronal/metabolism
MH  - Cell Cycle Proteins
MH  - Eukaryotic Initiation Factor-4E/metabolism
MH  - Eukaryotic Initiation Factors
MH  - Gene Deletion
MH  - *Gene Expression Regulation
MH  - Mice
MH  - *Nociception
MH  - Phosphoproteins/genetics/*metabolism
MH  - *Protein Biosynthesis
PMC - PMC4695384
OTO - NOTNLM
OT  - biochemistry
OT  - eIF4F complex
OT  - mRNA translation
OT  - mouse
OT  - neuroscience
OT  - pain
COIS- NS: Reviewing editor, eLife. The other authors declare that no competing 
      interests exist.
EDAT- 2015/12/19 06:00
MHDA- 2016/08/23 06:00
PMCR- 2015/12/19
CRDT- 2015/12/19 06:00
PHST- 2015/10/01 00:00 [received]
PHST- 2015/11/01 00:00 [accepted]
PHST- 2015/12/19 06:00 [entrez]
PHST- 2015/12/19 06:00 [pubmed]
PHST- 2016/08/23 06:00 [medline]
PHST- 2015/12/19 00:00 [pmc-release]
AID - e12002 [pii]
AID - 12002 [pii]
AID - 10.7554/eLife.12002 [doi]
PST - epublish
SO  - Elife. 2015 Dec 18;4:e12002. doi: 10.7554/eLife.12002.