ArticleScientific reports2017
Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 93 citations in OpenAlex.
- Functional connectivity signatures of NMDAR dysfunction in schizophrenia-integrating findings from imaging genetics and pharmaco-fMRI.Translational psychiatry · 2023Trial
- 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
- Demyelination-induced glutamatergic imbalance mediates hippocampal Hyperexcitability.Neurobiology of disease · 2025Article
- [Landau-Kleffner Syndrome: Current Etiopathogenesis and Management].Revista de neurologia · 2025Review
- Article
- Ligand distances as key predictors of pathogenicity and function in NMDA receptors.Human molecular genetics · 2025Article
- Article
- NMDA Receptors in Neurodevelopmental Disorders: Pathophysiology and Disease Models.International journal of molecular sciences · 2024Review
- Classification of Current Experimental Models of Epilepsy.Brain sciences · 2024Review
- In vitro human cell culture models in a bench-to-bedside approach to epilepsy.Epilepsia open · 2024Review
- 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
- Adapting the endoplasmic reticulum proteostasis rescues epilepsy-associated NMDA receptor variants.Acta pharmacologica Sinica · 2024Article
- A Frameshift Variant of GluN2A Identified in an Epilepsy Patient Results in NMDA Receptor Mistargeting.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- An integrated approach to evaluate the functional effects of disease-associated NMDA receptor variants.Neuropharmacology · 2023Article
- GRIN2A (NR2A): a gene contributing to glutamatergic involvement in schizophrenia.Molecular psychiatry · 2023Review
- Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes.Brain : a journal of neurology · 2023Article
- Systematic Assessment of Protein C-Termini Mutated in Human Disorders.Biomolecules · 2023Article
- Novel neuroactive steroids as positive allosteric modulators of NMDA receptors: mechanism, site of action, and rescue pharmacology on GRIN variants associated with neurological conditions.Cellular and molecular life sciences : CMLS · 2023Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Mutations in the N-methyl-D-aspartate receptor (NMDAR) gene GRIN2A cause epilepsy-aphasia syndrome (EAS), a spectrum of epileptic, cognitive and language disorders. Using bioinformatic and patient data we shortlisted 10 diverse missense mutations for characterisation. We used high-throughput calcium-flux assays and patch clamp recordings of transiently transfected HEK-293 cells for electrophysiological characterization, and Western blotting and confocal imaging to assay expression and surface trafficking. Mutations P79R, C231Y, G483R and M705V caused a significant reduction in glutamate and glycine agonist potency, whilst D731N was non-responsive. These mutants, along with E714K, also showed significantly decreased total protein levels and trafficking to the cell surface, whilst C436R was not trafficked at all. Crucially this reduced surface expression did not cause the reduced agonist response. We were able to rescue the phenotype of P79R, C231Y, G483R and M705V after treatment with a GluN2A-selective positive allosteric modulator. With our methodology we were not able to identify any functional deficits in mutations I814T, D933N and N976S located between the glutamate-binding domain and C-terminus. We show GRIN2A mutations affect the expression and function of the receptor in different ways. Careful molecular profiling of patients will be essential for future effective personalised treatment options.
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