, Volume 14, Issue 3, pp 728–733 | Cite as

Antidepressant Actions of Ketamine Mediated by the Mechanistic Target of Rapamycin, Nitric Oxide, and Rheb



The weeks/months it takes for traditional antidepressants to act pose an obstacle in the management of depression. Ketamine’s prompt and sustained antidepressant effects constitute a major advance. Multiple studies implicate glutamatergic signaling to protein synthesis machinery and synapse formation in ketamine’s antidepressant effects. Here we review evidence linking ketamine to glutamate receptor subtypes and protein homeostasis. We describe a signaling cascade wherein nitric oxide drives the formation of a ternary protein complex comprised of glyceraldehyde 3-phosphate dehydrogenase, seven in absentia homolog 1, and Ras homolog enriched in brain downstream of the glutamate N-methyl-D-aspartate receptor. Seven in absentia homolog 1 ubiquitylates and degrades Ras homolog enriched in brain leading to inhibition of mechanistic target of rapamycin. Ketamine inhibits this molecular cascade leading to activation of mechanistic target of rapamycin and, in turn, to antidepressant actions.


Ketamine Nitric oxide Glutamate receptor GAPDH Rheb mTOR 



We thank Susan McTeer for organizing the manuscript. This work was supported by USPHS grant DA000266. The authors declare no conflicts of interest.

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2017

Authors and Affiliations

  1. 1.The Solomon H. Snyder Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Psychiatry and Behavioral SciencesJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of Pharmacology and Molecular SciencesJohns Hopkins University School of MedicineBaltimoreUSA

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