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 Leonie Smith-Hicks, Shoaib Chowdhury, Walter Kaufmann, Dietmar Kuhl, Alexey G. Ryazanov, Richard L Huganir, David J Linden, Paul F Worley

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)70-83
Number of pages14
JournalNeuron
Volume59
Issue number1
DOIs
StatePublished - Jul 10 2008

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Fragile X Mental Retardation Protein
Peptide Elongation Factor 2
Metabotropic Glutamate Receptors
Metabotropic Glutamate 5 Receptor
Calcium-Calmodulin-Dependent Protein Kinases
Proteins
Dendrites
Synapses
Messenger RNA

Keywords

  • MOLNEURO
  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD. / Park, Sungjin; Park, Joo Min; Kim, Sangmok; Kim, Jin Ah; Shepherd, Jason D.; Smith-Hicks, Constance Leonie; Chowdhury, Shoaib; Kaufmann, Walter; Kuhl, Dietmar; Ryazanov, Alexey G.; Huganir, Richard L; Linden, David J; Worley, Paul F.

In: Neuron, Vol. 59, No. 1, 10.07.2008, p. 70-83.

Research output: Contribution to journalArticle

Park, Sungjin ; Park, Joo Min ; Kim, Sangmok ; Kim, Jin Ah ; Shepherd, Jason D. ; Smith-Hicks, Constance Leonie ; Chowdhury, Shoaib ; Kaufmann, Walter ; Kuhl, Dietmar ; Ryazanov, Alexey G. ; Huganir, Richard L ; Linden, David J ; Worley, Paul F. / Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD. In: Neuron. 2008 ; Vol. 59, No. 1. pp. 70-83.
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