Translational control of nociception via 4E-binding protein 1

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...

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Main Authors:	Khoutorsky, Arkady, Bonin, Robert P, Sorge, Robert E, Gkogkas, Christos G, Pawlowski, Sophie Anne, Jafarnejad, Seyed Mehdi, Pitcher, Mark H, Alain, Tommy, Perez-Sanchez, Jimena, Salter, Eric W, Martin, Loren, Ribeiro-da-Silva, Alfredo, De Koninck, Yves, Cervero, Fernando, Mogil, Jeffrey S, Sonenberg, Nahum
Format:	Online
Language:	English
Published:	eLife Sciences Publications, Ltd 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695384/

id	pubmed-4695384
recordtype	oai_dc
spelling	pubmed-46953842016-03-17 Translational control of nociception via 4E-binding protein 1 Khoutorsky, Arkady Bonin, Robert P Sorge, Robert E Gkogkas, Christos G Pawlowski, Sophie Anne Jafarnejad, Seyed Mehdi Pitcher, Mark H Alain, Tommy Perez-Sanchez, Jimena Salter, Eric W Martin, Loren Ribeiro-da-Silva, Alfredo De Koninck, Yves Cervero, Fernando Mogil, Jeffrey S Sonenberg, Nahum Biochemistry 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. eLife Sciences Publications, Ltd 2015-12-18 /pmc/articles/PMC4695384/ /pubmed/26678009 http://dx.doi.org/10.7554/eLife.12002 Text en http://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (http://creativecommons.org/publicdomain/zero/1.0/) .
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Khoutorsky, Arkady Bonin, Robert P Sorge, Robert E Gkogkas, Christos G Pawlowski, Sophie Anne Jafarnejad, Seyed Mehdi Pitcher, Mark H Alain, Tommy Perez-Sanchez, Jimena Salter, Eric W Martin, Loren Ribeiro-da-Silva, Alfredo De Koninck, Yves Cervero, Fernando Mogil, Jeffrey S Sonenberg, Nahum
spellingShingle	Khoutorsky, Arkady Bonin, Robert P Sorge, Robert E Gkogkas, Christos G Pawlowski, Sophie Anne Jafarnejad, Seyed Mehdi Pitcher, Mark H Alain, Tommy Perez-Sanchez, Jimena Salter, Eric W Martin, Loren Ribeiro-da-Silva, Alfredo De Koninck, Yves Cervero, Fernando Mogil, Jeffrey S Sonenberg, Nahum Translational control of nociception via 4E-binding protein 1
author_facet	Khoutorsky, Arkady Bonin, Robert P Sorge, Robert E Gkogkas, Christos G Pawlowski, Sophie Anne Jafarnejad, Seyed Mehdi Pitcher, Mark H Alain, Tommy Perez-Sanchez, Jimena Salter, Eric W Martin, Loren Ribeiro-da-Silva, Alfredo De Koninck, Yves Cervero, Fernando Mogil, Jeffrey S Sonenberg, Nahum
author_sort	Khoutorsky, Arkady
title	Translational control of nociception via 4E-binding protein 1
title_short	Translational control of nociception via 4E-binding protein 1
title_full	Translational control of nociception via 4E-binding protein 1
title_fullStr	Translational control of nociception via 4E-binding protein 1
title_full_unstemmed	Translational control of nociception via 4E-binding protein 1
title_sort	translational control of nociception via 4e-binding protein 1
description	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.
publisher	eLife Sciences Publications, Ltd
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695384/
_version_	1613518001624055808

Translational control of nociception via 4E-binding protein 1

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