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

Neuron. 2008 Jul 10;59(1):70-83. doi: 10.1016/j.neuron.2008.05.023.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Excitatory Postsynaptic Potentials / physiology
  • Excitatory Postsynaptic Potentials / radiation effects
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / physiology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / 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
  • Protein Biosynthesis / physiology*
  • Protein Biosynthesis / radiation effects
  • Protein Synthesis Inhibitors / pharmacology
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Receptors, AMPA / physiology*

Substances

  • 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