Dynamic regulation of phosphorylation of NMDA receptor GluN2B subunit tyrosine residues mediates ketamine rapid antidepressant effects.
Ke Wang, Xuan Tan, Kai-Mo Ding, Xue-Zhu Feng, Yu-Yu Zhao, Wei-Li Zhu, Guo-Hai Li, Su-Xia Li
Pharmacological Research July 1, 2024 DOI: 10.1016/j.phrs.2024.107236 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Ketamine |
| Duration | Within 1 hour after administration |
| Topics | Ketamine Esketamine |
| Keywords | Dephosphorylation Dynamic phosphorylation Nr2b Rapid antidepressant effects Ketamine infusion Mood disorder treatment Neuroscience brain science Neurobiology Receptor signaling |
| Citations | 5 |
| Post-publication review | 3 comments on PubPeer (opens in new tab) · last active August 2024 |
| Key findings | Ketamine's rapid antidepressant effects result from restoring NR2B phosphorylation homeostasis within and outside synapses in the medial prefrontal cortex. |
Abstract
The rapid antidepressant effects of ketamine depend on the N-methyl-D-aspartate (NMDA) receptor containing 2B subunit (NR2B), whose function is influenced by its phosphorylated regulation and distribution within and outside synapses. It remains unclear if ketamine's rapid onset of antidepressant effects relies on the dynamic phosphorylated regulation of NR2B within and outside synapses. Here, we show that ketamine rapidlyalleviated depression-like behaviors and normalized abnormal expression of pTyr1472NR2B and striatal-enriched protein tyrosine phosphatase (STEP) 61 within and outside synapses in the medial prefrontal cortex (mPFC) induced by chronic unpredictable stress (CUS) and conditional knockdown of STEP 61, a key phosphatase of NR2B, within 1 hour after administration Together, our results delineate the rapid initiation of ketamine's antidepressant effects results from the restoration of NR2B phosphorylation homeostasis within and outside synapses. The dynamic regulation of phosphorylation of NR2B provides a new perspective for developing new antidepressant strategies.