Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD

Sungjin Park; Joo Min Park; Sangmok Kim; Jin Ah Kim; Jason D. Shepherd; Constance L. Smith-Hicks; Shoaib Chowdhury; Walter Kaufmann; Dietmar Kuhl; Alexey G. Ryazanov; Richard L. Huganir; David J. Linden; Paul F. Worley

doi:10.1016/j.neuron.2008.05.023

Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD

Sungjin Park, Joo Min Park, Sangmok Kim, Jin Ah Kim, Jason D. Shepherd, Constance L. Smith-Hicks, Shoaib Chowdhury, Walter Kaufmann, Dietmar Kuhl, Alexey G. Ryazanov, Richard L. Huganir, David J. Linden, Paul F. Worley

Research output: Contribution to journal › Article › peer-review

384 Scopus citations

Abstract

Group I metabotropic glutamate receptors (mGluR) induce long-term depression (LTD) that requires protein synthesis. Here, we demonstrate that Arc/Arg3.1 is translationally induced within 5 min of mGluR activation, and this response is essential for mGluR-dependent LTD. The increase in Arc/Arg3.1 translation requires eEF2K, a Ca²⁺/calmodulin-dependent kinase that binds mGluR and dissociates upon mGluR activation, whereupon it phosphorylates eEF2. Phospho-eEF2 acts to slow the elongation step of translation and inhibits general protein synthesis but simultaneously increases Arc/Arg3.1 translation. Genetic deletion of eEF2K results in a selective deficit of rapid mGluR-dependent Arc/Arg3.1 translation and mGluR-LTD. This rapid translational mechanism is disrupted in the fragile X disease mouse (Fmr1 KO) in which mGluR-LTD does not require de novo protein synthesis but does require Arc/Arg3.1. We propose a model in which eEF2K-eEF2 and FMRP coordinately control the dynamic translation of Arc/Arg3.1 mRNA in dendrites that is critical for synapse-specific LTD.

Original language	English (US)
Pages (from-to)	70-83
Number of pages	14
Journal	Neuron
Volume	59
Issue number	1
DOIs	https://doi.org/10.1016/j.neuron.2008.05.023
State	Published - Jul 10 2008

Keywords

MOLNEURO
PROTEINS
SIGNALING

ASJC Scopus subject areas

Neuroscience(all)

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10.1016/j.neuron.2008.05.023

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Park, S., Park, J. M., Kim, S., Kim, J. A., Shepherd, J. D., Smith-Hicks, C. L., Chowdhury, S., Kaufmann, W., Kuhl, D., Ryazanov, A. G., Huganir, R. L., Linden, D. J., & Worley, P. F. (2008). Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD. Neuron, 59(1), 70-83. https://doi.org/10.1016/j.neuron.2008.05.023

Park, S, Park, JM, Kim, S, Kim, JA, Shepherd, JD, Smith-Hicks, CL, Chowdhury, S, Kaufmann, W, Kuhl, D, Ryazanov, AG, Huganir, RL , Linden, DJ & Worley, PF 2008, 'Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD', Neuron, vol. 59, no. 1, pp. 70-83. https://doi.org/10.1016/j.neuron.2008.05.023

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title = "Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD",

abstract = "Group I metabotropic glutamate receptors (mGluR) induce long-term depression (LTD) that requires protein synthesis. Here, we demonstrate that Arc/Arg3.1 is translationally induced within 5 min of mGluR activation, and this response is essential for mGluR-dependent LTD. The increase in Arc/Arg3.1 translation requires eEF2K, a Ca2+/calmodulin-dependent kinase that binds mGluR and dissociates upon mGluR activation, whereupon it phosphorylates eEF2. Phospho-eEF2 acts to slow the elongation step of translation and inhibits general protein synthesis but simultaneously increases Arc/Arg3.1 translation. Genetic deletion of eEF2K results in a selective deficit of rapid mGluR-dependent Arc/Arg3.1 translation and mGluR-LTD. This rapid translational mechanism is disrupted in the fragile X disease mouse (Fmr1 KO) in which mGluR-LTD does not require de novo protein synthesis but does require Arc/Arg3.1. We propose a model in which eEF2K-eEF2 and FMRP coordinately control the dynamic translation of Arc/Arg3.1 mRNA in dendrites that is critical for synapse-specific LTD.",

keywords = "MOLNEURO, PROTEINS, SIGNALING",

author = "Sungjin Park and Park, {Joo Min} and Sangmok Kim and Kim, {Jin Ah} and Shepherd, {Jason D.} and Smith-Hicks, {Constance L.} and Shoaib Chowdhury and Walter Kaufmann and Dietmar Kuhl and Ryazanov, {Alexey G.} and Huganir, {Richard L.} and Linden, {David J.} and Worley, {Paul F.}",

note = "Funding Information: This work was supported by NIMH grants MH053608 (P.F.W.), MH068830 (R.L.H.), MH51106 (D.J.L.), NIDA grant DA00266 (P.F.W.), NIA grant AG019890 (A.G.R.), GM057300 (A.G.R.), and FRAXA (W.K.). We thank Marlin Dehoff and Glory Harris for animal husbandry and David Lieberman for helpful discussions. ",

year = "2008",

month = jul,

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doi = "10.1016/j.neuron.2008.05.023",

language = "English (US)",

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T1 - Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD

AU - Park, Sungjin

AU - Park, Joo Min

AU - Kim, Sangmok

AU - Kim, Jin Ah

AU - Shepherd, Jason D.

AU - Smith-Hicks, Constance L.

AU - Chowdhury, Shoaib

AU - Kaufmann, Walter

AU - Kuhl, Dietmar

AU - Ryazanov, Alexey G.

AU - Huganir, Richard L.

AU - Linden, David J.

AU - Worley, Paul F.

N1 - Funding Information: This work was supported by NIMH grants MH053608 (P.F.W.), MH068830 (R.L.H.), MH51106 (D.J.L.), NIDA grant DA00266 (P.F.W.), NIA grant AG019890 (A.G.R.), GM057300 (A.G.R.), and FRAXA (W.K.). We thank Marlin Dehoff and Glory Harris for animal husbandry and David Lieberman for helpful discussions.

PY - 2008/7/10

Y1 - 2008/7/10

N2 - Group I metabotropic glutamate receptors (mGluR) induce long-term depression (LTD) that requires protein synthesis. Here, we demonstrate that Arc/Arg3.1 is translationally induced within 5 min of mGluR activation, and this response is essential for mGluR-dependent LTD. The increase in Arc/Arg3.1 translation requires eEF2K, a Ca2+/calmodulin-dependent kinase that binds mGluR and dissociates upon mGluR activation, whereupon it phosphorylates eEF2. Phospho-eEF2 acts to slow the elongation step of translation and inhibits general protein synthesis but simultaneously increases Arc/Arg3.1 translation. Genetic deletion of eEF2K results in a selective deficit of rapid mGluR-dependent Arc/Arg3.1 translation and mGluR-LTD. This rapid translational mechanism is disrupted in the fragile X disease mouse (Fmr1 KO) in which mGluR-LTD does not require de novo protein synthesis but does require Arc/Arg3.1. We propose a model in which eEF2K-eEF2 and FMRP coordinately control the dynamic translation of Arc/Arg3.1 mRNA in dendrites that is critical for synapse-specific LTD.

AB - Group I metabotropic glutamate receptors (mGluR) induce long-term depression (LTD) that requires protein synthesis. Here, we demonstrate that Arc/Arg3.1 is translationally induced within 5 min of mGluR activation, and this response is essential for mGluR-dependent LTD. The increase in Arc/Arg3.1 translation requires eEF2K, a Ca2+/calmodulin-dependent kinase that binds mGluR and dissociates upon mGluR activation, whereupon it phosphorylates eEF2. Phospho-eEF2 acts to slow the elongation step of translation and inhibits general protein synthesis but simultaneously increases Arc/Arg3.1 translation. Genetic deletion of eEF2K results in a selective deficit of rapid mGluR-dependent Arc/Arg3.1 translation and mGluR-LTD. This rapid translational mechanism is disrupted in the fragile X disease mouse (Fmr1 KO) in which mGluR-LTD does not require de novo protein synthesis but does require Arc/Arg3.1. We propose a model in which eEF2K-eEF2 and FMRP coordinately control the dynamic translation of Arc/Arg3.1 mRNA in dendrites that is critical for synapse-specific LTD.

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KW - PROTEINS

KW - SIGNALING

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JO - Neuron

JF - Neuron

SN - 0896-6273

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ER -

Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD

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