期刊
NEURON
卷 59, 期 1, 页码 70-83出版社
CELL PRESS
DOI: 10.1016/j.neuron.2008.05.023
关键词
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资金
- Howard Hughes Medical Institute Funding Source: Medline
- NIA NIH HHS [R01 AG019890, R01 AG019890-05, AG019890] Funding Source: Medline
- NIDA NIH HHS [P50 DA000266-37, DA00266, P50 DA000266] Funding Source: Medline
- NIGMS NIH HHS [R01 GM057300, R01 GM057300-05, GM057300] Funding Source: Medline
- NIMH NIH HHS [R01 MH053608-14, R29 MH051106, R37 MH051106-16, R01 MH051106, P50 MH068830, R37 MH051106, MH053608, P50 MH068830-05, R01 MH053608, MH068830, MH51106] Funding Source: Medline
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.
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