ArticleeLife2022
Excitatory and inhibitory D-serine binding to the NMDA receptor.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 16 citations in OpenAlex.
- Dextrorotatory kynurenine suppresses acute rejection through inhibiting M1 macrophage-mediated inflammation.EMBO molecular medicine · 2026Article
- Negr1 deficiency alters glutamate signalling and kynurenine pathway in a mouse model of psychiatric disorders.Scientific reports · 2026Article
- Activation of silent synapses driven by emerging technologies: mechanisms, disease associations, and prospects for clinical translation.Frontiers in synaptic neuroscience · 2026Review
- Exploring the Neurotherapeutic Potential of Bacillus-derived Macrolactins as NMDAR Antagonists for Alzheimer's Disease: Network Pharmacology and Molecular Modeling Insights.Current drug discovery technologies · 2026Article
- Pharmacological inhibition of PSPH reduces serine levels and epileptic seizures.Nature chemical biology · 2025Article
- Exploring NMDAR pathways in ischemic stroke: implications for neurotoxic and neuroprotective mechanisms and therapeutic strategies.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Role of Saponins fromMolecules (Basel, Switzerland) · 2025Article
- Regulation of NMDAR activation efficiency by environmental factors and subunit composition.The Journal of general physiology · 2025Article
- The Mechanisms of Magnesium in Sleep Disorders.Nature and science of sleep · 2025Review
- Advances and challenges in serine in the central nervous system: physicochemistry, physiology, and pharmacology.Metabolic brain disease · 2024Review
- Structural insights into NMDA receptor pharmacology.Biochemical Society transactions · 2023Review
- The Acute Effects and Mechanism of Ketamine on Nicotine-Induced Neurogenic Relaxation of the Corpus Cavernosum in Mice.International journal of molecular sciences · 2023Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
N-methyl-D-aspartate receptors (NMDARs) uniquely require binding of two different neurotransmitter agonists for synaptic transmission. D-serine and glycine bind to one subunit, GluN1, while glutamate binds to the other, GluN2. These agonists bind to the receptor's bi-lobed ligand-binding domains (LBDs), which close around the agonist during receptor activation. To better understand the unexplored mechanisms by which D-serine contributes to receptor activation, we performed multi-microsecond molecular dynamics simulations of the GluN1/GluN2A LBD dimer with free D-serine and glutamate agonists. Surprisingly, we observed D-serine binding to both GluN1 and GluN2A LBDs, suggesting that D-serine competes with glutamate for binding to GluN2A. This mechanism is confirmed by our electrophysiology experiments, which show that D-serine is indeed inhibitory at high concentrations. Although free energy calculations indicate that D-serine stabilizes the closed GluN2A LBD, its inhibitory behavior suggests that it either does not remain bound long enough or does not generate sufficient force for ion channel gating. We developed a workflow using pathway similarity analysis to identify groups of residues working together to promote binding. These conformation-dependent pathways were not significantly impacted by the presence of N-linked glycans, which act primarily by interacting with the LBD bottom lobe to stabilize the closed LBD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.