The Role of Eukaryotic Elongation Factor 2 Kinase in Rapid Antidepressant Action of Ketamine

      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 Ca2+/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.

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        • Kessler R.C.
        • Chiu W.T.
        • Demler O.
        • Merikangas K.R.
        • Walters E.E.
        Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication.
        Arch Gen Psychiatry. 2005; 62: 617-627
      1. Centers for Disease Control and Prevention (CDC) (2010): Web-based Injury Statistics Query and Reporting System (WISQARS). Atlanta, GA: National Center for Injury Prevention and Control, CDC. Available at:

        • Berman R.M.
        • Cappiello A.
        • Anand A.
        • Oren D.A.
        • Heninger G.R.
        • Charney D.S.
        • Krystal J.H.
        Antidepressant effects of ketamine in depressed patients.
        Biol Psychiatry. 2000; 47: 351-354
        • Furey M.L.
        • Drevets W.C.
        Antidepressant efficacy of the antimuscarinic drug scopolamine: A randomized, placebo-controlled clinical trial.
        Arch Gen Psychiatry. 2006; 63: 1121-1129
        • Price R.B.
        • Nock M.K.
        • Charney D.S.
        • Mathew S.J.
        Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression.
        Biol Psychiatry. 2009; 66: 522-526
        • Zarate Jr, C.A.
        • Singh J.B.
        • Carlson P.J.
        • Brutsche N.E.
        • Ameli R.
        • Luckenbaugh D.A.
        • Charney D.S.
        • Manji H.K.
        A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
        Arch Gen Psychiatry. 2006; 63: 856-864
        • Constantine-Paton M.
        • Cline H.T.
        LTP and activity-dependent synaptogenesis: The more alike they are, the more different they become.
        Curr Opin Neurobiol. 1998; 8: 139-148
        • Popoli M.
        • Yan Z.
        • McEwen B.S.
        • Sanacora G.
        The stressed synapse: The impact of stress and glucocorticoids on glutamate transmission.
        Nat Rev Neurosci. 2012; 13: 22-37
        • Sutton M.A.
        • Schuman E.M.
        Dendritic protein synthesis, synaptic plasticity, and memory.
        Cell. 2006; 127: 49-58
        • Autry A.E.
        • Adachi M.
        • Nosyreva E.
        • Na E.S.
        • Los M.F.
        • Cheng P.F.
        • et al.
        NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
        Nature. 2011; 475: 91-95
        • Chen B.
        • Dowlatshahi D.
        • MacQueen G.M.
        • Wang J.F.
        • Young L.T.
        Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.
        Biol Psychiatry. 2001; 50: 260-265
        • Adachi M.
        • Barrot M.
        • Autry A.E.
        • Theobald D.
        • Monteggia L.M.
        Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy.
        Biol Psychiatry. 2008; 63: 642-649
        • Monteggia L.M.
        • Barrot M.
        • Powell C.M.
        • Berton O.
        • Galanis V.
        • Gemelli T.
        • et al.
        Essential role of brain-derived neurotrophic factor in adult hippocampal function.
        Proc Natl Acad Sci U S A. 2004; 101: 10827-10832
        • Hoshaw B.A.
        • Malberg J.E.
        • Lucki I.
        Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects.
        Brain Res. 2005; 1037: 204-208
        • Shirayama Y.
        • Chen A.C.
        • Nakagawa S.
        • Russell D.S.
        • Duman R.S.
        Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression.
        J Neurosci. 2002; 22: 3251-3261
        • Duman R.S.
        • Monteggia L.M.
        A neurotrophic model for stress-related mood disorders.
        Biol Psychiatry. 2006; 59: 1116-1127
        • Sutton M.A.
        • Ito H.T.
        • Cressy P.
        • Kempf C.
        • Woo J.C.
        • Schuman E.M.
        Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis.
        Cell. 2006; 125: 785-799
        • Sutton M.A.
        • Wall N.R.
        • Aakalu G.N.
        • Schuman E.M.
        Regulation of dendritic protein synthesis by miniature synaptic events.
        Science. 2004; 304: 1979-1983
        • Kavalali E.T.
        • Chung C.
        • Khvotchev M.
        • Leitz J.
        • Nosyreva E.
        • Raingo J.
        • Ramirez D.M.
        Spontaneous neurotransmission: An independent pathway for neuronal signaling?.
        Physiology (Bethesda). 2011; 26: 45-53
        • Sutton M.A.
        • Taylor A.M.
        • Ito H.T.
        • Pham A.
        • Schuman E.M.
        Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis.
        Neuron. 2007; 55: 648-661
        • Ryazanov A.G.
        Elongation factor-2 kinase and its newly discovered relatives.
        FEBS Lett. 2002; 514: 26-29
        • Middelbeek J.
        • Clark K.
        • Venselaar H.
        • Huynen M.A.
        • van Leeuwen F.N.
        The alpha-kinase family: An exceptional branch on the protein kinase tree.
        Cell Mol Life Sci. 2010; 67: 875-890
        • Pigott C.R.
        • Mikolajek H.
        • Moore C.E.
        • Finn S.J.
        • Phippen C.W.
        • Werner J.M.
        • Proud C.G.
        Insights into the regulation of eukaryotic elongation factor 2 kinase and the interplay between its domains.
        Biochem J. 2012; 442: 105-118
        • Ryazanov A.G.
        • Rudkin B.B.
        • Spirin A.S.
        Regulation of protein synthesis at the elongation stage. New insights into the control of gene expression in eukaryotes.
        FEBS Lett. 1991; 285: 170-175
        • Ryazanov A.G.
        • Shestakova E.A.
        • Natapov P.G.
        Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation.
        Nature. 1988; 334: 170-173
        • Davidkova G.
        • Carroll R.C.
        Characterization of the role of microtubule-associated protein 1B in metabotropic glutamate receptor-mediated endocytosis of AMPA receptors in hippocampus.
        J Neurosci. 2007; 27: 13273-13278
        • Marin P.
        • Nastiuk K.L.
        • Daniel N.
        • Girault J.A.
        • Czernik A.J.
        • Glowinski J.
        • et al.
        Glutamate-dependent phosphorylation of elongation factor-2 and inhibition of protein synthesis in neurons.
        J Neurosci. 1997; 17: 3445-3454
        • Park S.
        • Park J.M.
        • Kim S.
        • Kim J.A.
        • Shepherd J.D.
        • Smith-Hicks C.L.
        • et al.
        Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD.
        Neuron. 2008; 59: 70-83
        • Scheetz A.J.
        • Nairn A.C.
        • Constantine-Paton M.
        NMDA receptor-mediated control of protein synthesis at developing synapses.
        Nat Neurosci. 2000; 3: 211-216
        • Verpelli C.
        • Piccoli G.
        • Zibetti C.
        • Zanchi A.
        • Gardoni F.
        • Huang K.
        • et al.
        Synaptic activity controls dendritic spine morphology by modulating eEF2-dependent BDNF synthesis.
        J Neurosci. 2010; 30: 5830-5842
        • Asaki C.
        • Usuda N.
        • Nakazawa A.
        • Kametani K.
        • Suzuki T.
        Localization of translational components at the ultramicroscopic level at postsynaptic sites of the rat brain.
        Brain Res. 2003; 972: 168-176
        • Barrera I.
        • Hernandez-Kelly L.C.
        • Castelan F.
        • Ortega A.
        Glutamate-dependent elongation factor-2 phosphorylation in Bergmann glial cells.
        Neurochem Int. 2008; 52: 1167-1175
        • Scheetz A.J.
        • Constantine-Paton M.
        NMDA receptor activation-responsive phosphoproteins in the developing optic tectum.
        J Neurosci. 1996; 16: 1460-1469
        • Huber K.M.
        • Kayser M.S.
        • Bear M.F.
        Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression.
        Science. 2000; 288: 1254-1257
        • Browne G.J.
        • Finn S.G.
        • Proud C.G.
        Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398.
        J Biol Chem. 2004; 279: 12220-12231
        • Diggle T.A.
        • Subkhankulova T.
        • Lilley K.S.
        • Shikotra N.
        • Willis A.E.
        • Redpath N.T.
        Phosphorylation of elongation factor-2 kinase on serine 499 by cAMP-dependent protein kinase induces Ca2+/calmodulin-independent activity.
        Biochem J. 2001; 353: 621-626
        • Pyr Dit Ruys S.
        • Wang X.
        • Smith E.M.
        • Herinckx G.
        • Hussain N.
        • Rider M.H.
        • Vertommen D.
        • Proud CG
        Identification of autophosphorylation sites in eukaryotic elongation factor-2 kinase.
        Biochem J. 2012; 442: 681-692
        • Tavares C.D.
        • O’Brien J.P.
        • Abramczyk O.
        • Devkota A.K.
        • Shores K.S.
        • Ferguson S.B.
        • et al.
        Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence.
        Biochemistry. 2012; 51: 2232-2245
        • Wang X.
        • Li W.
        • Williams M.
        • Terada N.
        • Alessi D.R.
        • Proud C.G.
        Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase.
        EMBO J. 2001; 20: 4370-4379