ArticleAmerican journal of human genetics2016
Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains.
Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 122 papers.
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Who cites it
122 citing papers in PubMed, 178 citations in OpenAlex.
- Neuroprotection by YZG-331 in postoperative cognitive dysfunctionActa pharmaceutica Sinica. B · 2026Article
- Subconductance states in NMDA receptor variants are CaResearch square · 2026Article
- Hypoxia-inducible factor signaling regulates embryonic interneuron development, GRIN2B expression and adult cortical function.Developmental cell · 2026Article
- AMCF-RDP: a self-attention-based multi-source and cascade framework for the identification of drug-protein relationships.Molecular diversity · 2026Article
- The Role of Disulfide Bonds in the GluN1 Subunit in the Early Trafficking and Functional Properties of GluN1/GluN2 and GluN1/GluN3 NMDA Receptors.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Inhibition of GluN2B-containing N-methyl-D-aspartate receptors by radiprodil.Brain : a journal of neurology · 2026Article
- HDAC6 Inhibition Drives Synaptic Protein Acetylation and Enhances Long-Term Memory in Mice.Molecular neurobiology · 2025Article
- Clinical and Molecular Genetic Characterization of Landau Kleffner Syndrome: An Observational Cohort and Experimental Study.Annals of neurology · 2025Observational
- De-risking seizure liability: integrating adverse outcome pathways (AOPs), new approach methodologies (NAMs), and in silico approaches while highlighting knowledge gaps.Toxicological sciences : an official journal of the Society of Toxicology · 2025Review
- GRIN2B disease-associated mutations disrupt the function of BK channels and NMDA receptor signaling nanodomains.The Journal of general physiology · 2025Article
- Disruption ofThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Distinct Regulation of Early Trafficking of the NMDA Receptors by the Ligand-Binding Domains of the GluN1 and GluN2A Subunits.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Ligand distances as key predictors of pathogenicity and function in NMDA receptors.Human molecular genetics · 2025Article
- Spatiotemporal differential regulation of extrasynaptic GluN2B receptor subunits and PSA-NCAM in brain aging and Alzheimer's disease.Frontiers in neuroscience · 2025Article
- L-serine treatment in a patient with refractory epilepsy due to a GRIN2A missense mutation.Acta neurologica Belgica · 2024Article
- Mechanisms of Action Underlying Conductance-Modifying Positive Allosteric Modulators of the NMDA Receptor.Molecular pharmacology · 2024Article
- Developmental and epileptic encephalopathies.Nature reviews. Disease primers · 2024Review
- Characterization of Mice Carrying a Neurodevelopmental Disease-Associated GluN2B(L825V) Variant.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology.Physiological research · 2024Review
- Rescuing tri-heteromeric NMDA receptor function: the potential of pregnenolone-sulfate in loss-of-function GRIN2B variants.Cellular and molecular life sciences : CMLS · 2024Article
62 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
Abstract
Epilepsy and intellectual disability are associated with rare variants in the GluN2A and GluN2B (encoded by GRIN2A and GRIN2B) subunits of the N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel with essential roles in brain development and function. By assessing genetic variation across GluN2 domains, we determined that the agonist binding domain, transmembrane domain, and the linker regions between these domains were particularly intolerant to functional variation. Notably, the agonist binding domain of GluN2B exhibited significantly more variation intolerance than that of GluN2A. To understand the ramifications of missense variation in the agonist binding domain, we investigated the mechanisms by which 25 rare variants in the GluN2A and GluN2B agonist binding domains dysregulated NMDAR activity. When introduced into recombinant human NMDARs, these rare variants identified in individuals with neurologic disease had complex, and sometimes opposing, consequences on agonist binding, channel gating, receptor biogenesis, and forward trafficking. Our approach combined quantitative assessments of these effects to estimate the overall impact on synaptic and non-synaptic NMDAR function. Interestingly, similar neurologic diseases were associated with both gain- and loss-of-function variants in the same gene. Most rare variants in GluN2A were associated with epilepsy, whereas GluN2B variants were associated with intellectual disability with or without seizures. Finally, discerning the mechanisms underlying NMDAR dysregulation by these rare variants allowed investigations of pharmacologic strategies to correct NMDAR function.
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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.