PMID:18614030

Citation	Park, S, Park, JM, Kim, S, Kim, JA, Shepherd, JD, Smith-Hicks, CL, Chowdhury, S, Kaufmann, W, Kuhl, D, Ryazanov, AG, Huganir, RL, Linden, DJ and Worley, PF (2008) Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 59:70-83
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.
Links	PubMed PMC2743934 Online version:10.1016/j.neuron.2008.05.023
Keywords	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
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:FMR1	involved_in	GO:0099578: regulation of translation at postsynapse, modulating synaptic transmission	ECO:0000315: mutant phenotype evidence used in manual assertion		P	occurs_in:(CL:0002608) regulates_translation_of:(ENSEMBL:ENSMUSG00000022602)	Seeded From UniProt	complete

References

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