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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antidepressive Agents / pharmacology
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Antidepressive Agents / therapeutic use*
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Cells, Cultured
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Cerebral Cortex / cytology
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Cysteine / analogs & derivatives
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Cysteine / pharmacology
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Depression / drug therapy*
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Disease Models, Animal
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Embryo, Mammalian
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Exploratory Behavior / drug effects
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Female
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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HEK293 Cells
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Humans
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Ketamine / pharmacology
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Ketamine / therapeutic use*
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Male
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Mice, Inbred C57BL
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Mice, Knockout
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Monomeric GTP-Binding Proteins / genetics
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Monomeric GTP-Binding Proteins / metabolism*
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N-Methylaspartate / pharmacology
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Neurons / drug effects
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Neuropeptides / genetics
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Neuropeptides / metabolism*
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Nitric Oxide / genetics
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Nitric Oxide / metabolism
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Nitric Oxide Synthase Type I / deficiency
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Nitric Oxide Synthase Type I / genetics
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Nitric Oxide Synthase Type II / deficiency
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Nitric Oxide Synthase Type II / genetics
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Pregnancy
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Proteolysis / drug effects*
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Ras Homolog Enriched in Brain Protein
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S-Nitrosothiols / pharmacology
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Signal Transduction / drug effects
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Swimming / psychology
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
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Time Factors
Substances
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Antidepressive Agents
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Neuropeptides
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Ras Homolog Enriched in Brain Protein
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Rheb protein, mouse
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S-Nitrosothiols
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Nitric Oxide
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N-Methylaspartate
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Ketamine
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S-nitrosocysteine
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Nitric Oxide Synthase Type I
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Nitric Oxide Synthase Type II
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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Monomeric GTP-Binding Proteins
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Cysteine