PMID- 23062356
OWN - NLM
STAT- MEDLINE
DCOM- 20131029
LR  - 20211021
IS  - 1873-2402 (Electronic)
IS  - 0006-3223 (Print)
IS  - 0006-3223 (Linking)
VI  - 73
IP  - 12
DP  - 2013 Jun 15
TI  - The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action 
      of ketamine.
PG  - 1199-203
LID - S0006-3223(12)00778-0 [pii]
LID - 10.1016/j.biopsych.2012.09.006 [doi]
AB  - Major depressive disorder is a devastating mental disorder. Current 
      antidepressant medications can be effective for some patients with depression; 
      however, these drugs exert mood-elevating effects only after prolonged 
      administration, and a sizable fraction of the patient population fails to respond 
      to treatment. There is an urgent need for faster-acting antidepressants with 
      reliable treatment outcomes and sustained efficacy for individuals with 
      depression, in particular those contemplating suicide. Recent clinical studies 
      report that ketamine, an ionotropic glutamatergic N-methyl-D-aspartate (NMDA) 
      receptor blocker, shows fast-acting antidepressant action, thus bringing fresh 
      perspective into preclinical studies investigating novel antidepressant targets 
      and treatments. Our recent studies show that the effects of ketamine are 
      dependent on brain-derived neurotrophic factor (BDNF) and subsequent activation 
      of the high-affinity BDNF receptor, TrkB. Our findings also suggest that the 
      fast-acting antidepressant effects of ketamine require rapid protein translation, 
      but not transcription, resulting in robust increases in dendritic BDNF protein 
      levels that are important for the behavioral effect. These findings also uncover 
      eukaryotic elongation factor 2 kinase (eEF2K), a Ca(2)(+)/calmodulin dependent 
      serine/threonine kinase that phosphorylates eEF2 and regulates the elongation 
      step of protein translation, as a major molecular substrate mediating the rapid 
      antidepressant effect of ketamine. Our results show that ketamine-mediated 
      suppression of resting NMDA receptor activity leads to inhibition of eEF2 kinase 
      and subsequent dephosphorylation of eEF2 and augmentation of BDNF synthesis. This 
      article outlines our recent studies on the synaptic mechanisms that underlie 
      ketamine action, in particular the properties of eEF2K as a potential 
      antidepressant target.
CI  - Copyright (c) 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All 
      rights reserved.
FAU - Monteggia, Lisa M
AU  - Monteggia LM
AD  - Department of Psychiatry, The University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA. lisa.monteggia@utsouthwestern.edu
FAU - Gideons, Erinn
AU  - Gideons E
FAU - Kavalali, Ege T
AU  - Kavalali ET
LA  - eng
GR  - R01 MH066198/MH/NIMH NIH HHS/United States
GR  - R01 MH070727/MH/NIMH NIH HHS/United States
GR  - MH066198/MH/NIMH NIH HHS/United States
GR  - MH070727/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20121011
PL  - United States
TA  - Biol Psychiatry
JT  - Biological psychiatry
JID - 0213264
RN  - 0 (Antidepressive Agents)
RN  - 690G0D6V8H (Ketamine)
RN  - EC 2.7.11.20 (Elongation Factor 2 Kinase)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/*pharmacology/therapeutic use
MH  - Depression/drug therapy
MH  - Elongation Factor 2 Kinase/*metabolism
MH  - Gene Expression Regulation, Enzymologic/*drug effects
MH  - Humans
MH  - Ketamine/*pharmacology/therapeutic use
PMC - PMC3574622
MID - NIHMS414334
EDAT- 2012/10/16 06:00
MHDA- 2013/10/30 06:00
PMCR- 2014/06/15
CRDT- 2012/10/16 06:00
PHST- 2012/07/02 00:00 [received]
PHST- 2012/08/30 00:00 [revised]
PHST- 2012/09/05 00:00 [accepted]
PHST- 2012/10/16 06:00 [entrez]
PHST- 2012/10/16 06:00 [pubmed]
PHST- 2013/10/30 06:00 [medline]
PHST- 2014/06/15 00:00 [pmc-release]
AID - S0006-3223(12)00778-0 [pii]
AID - 10.1016/j.biopsych.2012.09.006 [doi]
PST - ppublish
SO  - Biol Psychiatry. 2013 Jun 15;73(12):1199-203. doi: 
      10.1016/j.biopsych.2012.09.006. Epub 2012 Oct 11.