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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 Ca(2+)/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.
AuthorsSungjin 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
JournalNeuron (Neuron) Vol. 59 Issue 1 Pg. 70-83 (Jul 10 2008) ISSN: 1097-4199 [Electronic] United States
PMID18614030 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Cytoskeletal Proteins
  • Excitatory Amino Acid Agents
  • Nerve Tissue Proteins
  • Peptide Elongation Factor 2
  • Protein Synthesis Inhibitors
  • Receptors, AMPA
  • activity regulated cytoskeletal-associated protein
  • Fragile X Mental Retardation Protein
  • Cycloheximide
  • glutamate receptor ionotropic, AMPA 1
Topics
  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Cycloheximide (pharmacology)
  • Cytoskeletal Proteins (metabolism)
  • Dose-Response Relationship, Radiation
  • Electric Stimulation (methods)
  • Excitatory Amino Acid Agents (pharmacology)
  • Excitatory Postsynaptic Potentials (drug effects, physiology, radiation effects)
  • Fragile X Mental Retardation Protein (genetics, physiology)
  • Gene Expression Regulation (drug effects, radiation effects)
  • Hippocampus (cytology)
  • In Vitro Techniques
  • Long-Term Potentiation (physiology)
  • Male
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Nerve Tissue Proteins (metabolism)
  • Neurons (physiology)
  • Patch-Clamp Techniques
  • Peptide Elongation Factor 2 (physiology)
  • Protein Biosynthesis (drug effects, physiology, radiation effects)
  • Protein Synthesis Inhibitors (pharmacology)
  • Protein Transport (drug effects, physiology)
  • Receptors, AMPA (physiology)

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