The role of eEF2 kinase in the rapid antidepressant actions of ketamine

Adv Pharmacol. 2020;89:79-99. doi: 10.1016/bs.apha.2020.04.005. Epub 2020 May 22.

Abstract

Major depressive disorder is a prevalent and serious form of mental illness. While traditional antidepressants ameliorate some of the symptoms associated with depression, the onset of action typically takes several weeks leaving severely depressed individuals vulnerable to self-injurious behavior and possibly suicide. There has been a major unmet need for the development of pharmacological therapies that can quickly alleviate symptoms associated with depression. Clinical data shows that a single sub-psychomimetic dose of ketamine, a noncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid antidepressant responses in patients with treatment-resistant major depressive disorder. We have studied key signaling pathways and synaptic mechanisms underlying the rapid antidepressant action of ketamine. Our studies show ketamine blocks synaptic NMDA receptors involved in spontaneous synaptic transmission, which deactivates calcium/calmodulin-dependent kinase eukaryotic elongation factor 2 kinase (eEF2K), resulting in dephosphorylation of eukaryotic elongation factor 2 (eEF2), and the subsequent desuppression of brain-derived neurotrophic factor (BDNF) protein synthesis in the hippocampus. This signaling pathway then potentiates synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor responses that results in a novel form of synaptic potentiation which corresponds with antidepressant efficacy. In this chapter, we focus on our studies examining ketamine's action and the instructive role of eEF2K in rapid antidepressant action. Our recent studies highlight eEF2K as a major molecular substrate mediating synaptic plasticity and the rapid antidepressant effects of ketamine.

Keywords: BDNF; Ketamine; NMDA receptor; Protein translation; Rapid antidepressant; Spontaneous neurotransmission; Synaptic homeostasis; eEF2; eEF2K.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Depression / drug therapy
  • Depression / physiopathology
  • Elongation Factor 2 Kinase / metabolism*
  • Humans
  • Ketamine / pharmacology*
  • Ketamine / therapeutic use
  • Neuronal Plasticity / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • Antidepressive Agents
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine
  • Elongation Factor 2 Kinase