title: Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation.
abstract: As traditional antidepressants act only after weeks/months, the discovery that ketamine, an antagonist of glutamate/N-methyl-D-aspartate (NMDA) receptors, elicits antidepressant actions in hours has been transformative. Its mechanism of action has been elusive, though enhanced mammalian target of rapamycin (mTOR) signaling is a major feature. We report a novel signaling pathway wherein NMDA receptor activation stimulates generation of nitric oxide (NO), which S-nitrosylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Nitrosylated GAPDH complexes with the ubiquitin-E3-ligase Siah1 and Rheb, a small G protein that activates mTOR. Siah1 degrades Rheb leading to reduced mTOR signaling, while ketamine, conversely, stabilizes Rheb that enhances mTOR signaling. Drugs selectively targeting components of this pathway may offer novel approaches to the treatment of depression.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Harraz
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Tyagi
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Cortés
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007649:Ketamine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics; D011247:Pregnancy; D059748:Proteolysis / Q000187:drug effects*; D000076205:Ras Homolog Enriched in Brain Protein; D026403:S-Nitrosothiols / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013550:Swimming / Q000523:psychology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D026403:S-Nitrosothiols; D009569:Nitric Oxide; D016202:N-Methylaspartate; D007649:Ketamine; C021315:S-nitrosocysteine; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D003545:Cysteine