Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD.
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.
Park
Sungjin
S
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 20205, USA.
Park
Joo Min
JM
Kim
Sangmok
S
Kim
Jin-Ah
JA
Shepherd
Jason D
JD
Smith-Hicks
Constance L
CL
Chowdhury
Shoaib
S
Kaufmann
Walter
W
Kuhl
Dietmar
D
Ryazanov
Alexey G
AG
Huganir
Richard L
RL
Linden
David J
DJ
Worley
Paul F
PF
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D020652:Peptide Elongation Factor 2 / Q000502:physiology*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D018091:Receptors, AMPA / Q000502:physiology*
D003513:Cycloheximide; D003598:Cytoskeletal Proteins; D018683:Excitatory Amino Acid Agents; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D020652:Peptide Elongation Factor 2; D011500:Protein Synthesis Inhibitors; D018091:Receptors, AMPA; C092069:activity regulated cytoskeletal-associated protein