Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD

被引：410

作者：

Park, Sungjin ^{[1
]}

Park, Joo Min ^{[1
]}

Kim, Sangmok ^{[1
]}

Kim, Jin-Ah ^{[1
]}

Shepherd, Jason D. ^{[4
]}

Smith-Hicks, Constance L. ^{[2
]}

Chowdhury, Shoaib ^{[1
]}

Kaufmann, Walter ^{[2
]}

Kuhl, Dietmar ^{[5
]}

Ryazanov, Alexey G. ^{[6
]}

Huganir, Richard L. ^{[1
,3
]}

Linden, David J. ^{[1
]}

Worley, Paul F. ^{[1
,2
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Neurosci, Bethesda, MD 20205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Neurol, Bethesda, MD 20205 USA

[3] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Bethesda, MD 20205 USA

[4] MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA

[5] Free Univ Berlin, Dept Biol Chem Pharm, D-14195 Berlin, Germany

[6] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pharmacol, Piscataway, NJ 08854 USA

来源：

NEURON | 2008年 / 59卷 / 01期

关键词：

D O I：

10.1016/j.neuron.2008.05.023

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：70 / 83

页数：14

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