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