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.
|
Authors | 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 |
Journal | Neuron
(Neuron)
Vol. 59
Issue 1
Pg. 70-83
(Jul 10 2008)
ISSN: 1097-4199 [Electronic] United States |
PMID | 18614030
(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)
|