ArticlePLoS genetics2017
Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology.
Article in PLoS genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.
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Who cites it
95 citing papers in PubMed, 127 citations in OpenAlex.
- 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
- Inhibition of GluN2B-containing N-methyl-D-aspartate receptors by radiprodil.Brain : a journal of neurology · 2026Article
- New advances in small molecule drugs targeting NMDA receptors.Acta pharmacologica Sinica · 2026Review
- Disruption ofThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Regulation of NMDAR activation efficiency by environmental factors and subunit composition.The Journal of general physiology · 2025Article
- Clinical phenotype and functional influence of GRIN2A variants in epilepsy-aphasia syndrome.Epilepsia open · 2024Article
- Nanotechnology in Pain Management.Pharmaceutics · 2024Review
- Src dependency of the regulation of LTP by alternative splicing ofPhilosophical transactions of the Royal Society of London. Series B, Biological sciences · 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
- De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor.Cellular and molecular life sciences : CMLS · 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
- Disease-associated nonsense and frame-shift variants resulting in the truncation of the GluN2A or GluN2B C-terminal domain decrease NMDAR surface expression and reduce potentiating effects of neurosteroids.Cellular and molecular life sciences : CMLS · 2024Article
- Classification of missense variants in the N-methyl-d-aspartate receptor GRIN gene family as gain- or loss-of-function.Human molecular genetics · 2023Article
- Binding and Dynamics Demonstrate the Destabilization of Ligand Binding for the S688Y Mutation in the NMDA Receptor GluN1 Subunit.Molecules (Basel, Switzerland) · 2023Article
- Functional effects of disease-associated variants reveal that the S1-M1 linker of the NMDA receptor critically controls channel opening.Cellular and molecular life sciences : CMLS · 2023Article
- Two gates mediate NMDA receptor activity and are under subunit-specific regulation.Nature communications · 2023Article
- N-methyl-D-aspartate receptor hypofunction as a potential contributor to the progression and manifestation of many neurological disorders.Frontiers in molecular neuroscience · 2023Review
- Complex functional phenotypes of NMDA receptor disease variants.Molecular psychiatry · 2022Article
35 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
18 authors at 5 institutions in 3 countries.
Funding
Abstract
N-methyl-D-aspartate receptors (NMDARs), ligand-gated ionotropic glutamate receptors, play key roles in normal brain development and various neurological disorders. Here we use standing variation data from the human population to assess which protein domains within NMDAR GluN1, GluN2A and GluN2B subunits show the strongest signal for being depleted of missense variants. We find that this includes the GluN2 pre-M1 helix and linker between the agonist-binding domain (ABD) and first transmembrane domain (M1). We then evaluate the functional changes of multiple missense mutations in the NMDAR pre-M1 helix found in children with epilepsy and developmental delay. We find mutant GluN1/GluN2A receptors exhibit prolonged glutamate response time course for channels containing 1 or 2 GluN2A-P552R subunits, and a slow rise time only for receptors with 2 mutant subunits, suggesting rearrangement of one GluN2A pre-M1 helix is sufficient for rapid activation. GluN2A-P552R and analogous mutations in other GluN subunits increased the agonist potency and slowed response time course, suggesting a functionally conserved role for this residue. Although there is no detectable change in surface expression or open probability for GluN2A-P552R, the prolonged response time course for receptors that contained GluN2A-P552R increased charge transfer for synaptic-like activation, which should promote excitotoxic damage. Transfection of cultured neurons with GluN2A-P552R prolonged EPSPs, and triggered pronounced dendritic swelling in addition to excitotoxicity, which were both attenuated by memantine. These data implicate the pre-M1 region in gating, provide insight into how different subunits contribute to gating, and suggest that mutations in the pre-M1 helix can compromise neuronal health. Evaluation of FDA-approved NMDAR inhibitors on the mutant NMDAR-mediated current response and neuronal damage provides a potential clinical path to treat individuals harboring similar mutations in NMDARs.
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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.