Calcium/Calmodulin-Dependent Protein Kinase II and Eukaryotic Elongation Factor 2 Kinase Pathways Mediate the Antidepressant Action of Ketamine

Adaikkan, Chinnakkaruppan; Taha, Elham; Barrera, Iliana; David, Orit; Rosenblum, Kobi

doi:10.1016/j.biopsych.2017.11.028

Cited by 63 publications

(64 citation statements)

References 59 publications

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“…Ketamine has been shown to regulate CaMKII, eukaryotic elongation factor 2 kinase (Adaikkan et al, 2018), GSK3b (Beurel et al, 2016), and the phosphorylation of GluR1 subunits (Zhang et al, 2016), altering the expression, composition, and trafficking of AMPARs to the postsynaptic membrane. The blocking of AMPARs abolishes the ketamine-induced BDNF release and phosphorylation of MAPK in primary neuronal cultures, suggesting that these processes are dependent on increased glutamatergic signaling (Lepack et al, 2016).…”

Section: Examining Rapid Antidepressant Effects Through Encodingmentioning

confidence: 99%

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Rantamäki

Kohtala

2020

Pharmacol Rev

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Brain and Mind Doctoral Program (S.K.), the Orion Research Foundation (S.K.), and the Emil Aaltonen foundation (S.K.). T.R. and S.K. are listed as coinventors on a patent application, wherein new tools enabling the development of rapid-acting antidepressants and the efficacy monitors thereof are disclosed based on the basic principles of ENCORE-D. T.R. and S.K. have assigned their patent rights to the University of Helsinki but will share a percentage of any royalties that may be received by the University of Helsinki.

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Section: Examining Rapid Antidepressant Effects Through Encodingmentioning

confidence: 99%

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Rantamäki

Kohtala

2020

Pharmacol Rev

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“…To test directly if D1 receptor activation increases protein synthesis in an eEF2K/eEF2 pathway-dependent manner, we used primary cultures from eEF2K-KO mice. These mice show no eEF2 phosphorylation, but display normal phosphorylation of other translation factors (Adaikkan et al, 2018).…”

Section: D1 Receptor Activation Increases Protein Synthesis In Neuronmentioning

confidence: 96%

“…signaling cascades. This includes eEF2 dephosphorylation in neurons, in the soma and especially in dendrites, which is likely to contribute to the observed increase in polypeptide elongation and expression of BDNF and synapsin 2B (Adaikkan et al, 2018, Autry et al, 2011, Belelovsky et al, 2009, Gildish et al, 2012, Im et al, 2009, Ma et al, 2014, Park et al, 2008, Taha et al, 2013.…”

Section: Nmdar-d1 Partnership Induces Translational Changes Via Erk Amentioning

confidence: 99%

“…Recent studies involving manipulation of eEF2K activity have been a field of intense research, ranging from addiction Caron, 2015, Werner et al, 2018) and depression. Indeed, eEF2K serves as a target for the antidepressant ketamine, and has a role also in the progression of neurodegenerative diseases (Adaikkan et al, 2018, Heise et al, 2017, Jan et al, 2018, Kokkinou et al, 2018, Zang et al, 2018.…”

Section: Nmdar-d1 Partnership Induces Translational Changes Via Erk Amentioning

confidence: 99%

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MEK/mTOR-dependent D1 dopamine receptor activation induces local protein synthesis via eEF2 dephosphorylation in neurons

David

Barrera

Koltun

et al. 2018

Preprint

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One-sentence summary: D1 receptor activation increases protein synthesis in dendrites by inactivating eEF2K in an ERK2/mTOR-dependent manner. AbstractNeuromodulators in general, and dopamine in particular, define brain and neuronal states in different ways including regulation of global and local mRNA translation. Yet, the signaling pathways underlying the effects of dopamine on mRNA translation are not clear. Here, using genetic, pharmacologic, biochemical, and imaging methods, we tested the hypothesis that dopamine regulates phosphorylation of the eukaryotic elongation factor 2 (eEF2). We found that activation of dopamine receptor D1 but not D2 leads to rapid dephosphorylation of eEF2 at Thr 56 in cortical primary neuronal culture and in vivo in a time-dependent manner. Additionally, NMDA receptor, mTOR, and ERK pathways are upstream to the D1 receptor-dependent eEF2 dephosphorylation and essential for it. Furthermore, D1 receptor activation resulted in a major reduction in dendritic eEF2 phosphorylation levels together with a correlative increase in local mRNA translation. These results reveal the role of eEF2 in dopamine regulation of local mRNA translation in neurons.

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“…Mechanistically, both conventional antidepressants and ketamine promoted neural plasticity, including increased expression of brain-derived neurotrophic factor (BDNF; Moda-Sava et al, 2019), activation of cAMP response element-binding protein (CREB; Duman and Voleti, 2012;Reus et al, 2016), and activation of mammalian target of rapamycin (mTOR) signaling in the mPFC (Li et al, 2010). Rapid and persistent enhancement of neural plasticity, for example, via immediate suppression of eukaryotic elongation factor 2 (eEF2) or Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) signaling to induce global protein synthesis in the hippocampus, is also required for the rapid antidepressant activity of ketamine (Monteggia et al, 2013;Taha et al, 2013;Adaikkan et al, 2018). Conversely, impairment of neural plasticity is fundamental for the development of depression (Duman, 2002;Quiroz and Manji, 2002;Liu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

A Brain Signaling Framework for Stress-Induced Depression and Ketamine Treatment Elucidated by Phosphoproteomics

Xiao

Luo

Yang

et al. 2020

Front. Cell. Neurosci.

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Depression is a common affective disorder characterized by significant and persistent low mood. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, is reported to have a rapid and durable antidepressant effect, but the mechanisms are unclear. Protein phosphorylation is a post-translational modification that plays a crucial role in cell signaling. Thus, we present a phosphoproteomics approach to investigate the mechanisms underlying stress-induced depression and the rapid antidepressant effect of ketamine in mice. We analyzed the phosphoprotein changes induced by chronic unpredictable mild stress (CUMS) and ketamine treatment in two known mood control centers, the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). We initially obtained >8,000 phosphorylation sites. Quantitation revealed 3,988 sites from the mPFC and 3,196 sites from the NAc. Further analysis revealed that changes in synaptic transmission-related signaling are a common feature. Notably, CUMS-induced changes were reversed by ketamine treatment, as shown by the analysis of commonly altered sites. Ketamine also induced specific changes, such as alterations in synapse organization, synaptic transmission, and enzyme binding. Collectively, our findings establish a signaling framework for stress-induced depression and the rapid antidepressant effect of ketamine.

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Calcium/Calmodulin-Dependent Protein Kinase II and Eukaryotic Elongation Factor 2 Kinase Pathways Mediate the Antidepressant Action of Ketamine

Cited by 63 publications

References 59 publications

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

MEK/mTOR-dependent D1 dopamine receptor activation induces local protein synthesis via eEF2 dephosphorylation in neurons

A Brain Signaling Framework for Stress-Induced Depression and Ketamine Treatment Elucidated by Phosphoproteomics

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