ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Specific sites within the ligand-binding domain and ion channel linkers modulate NMDA receptor gating.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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57 citing papers in PubMed, 70 citations in OpenAlex.
- Subconductance states in NMDA receptor variants are CaResearch square · 2026Article
- Discovery of novel GluN1/GluN3A NMDA receptor inhibitors using a deep learning-based method.Acta pharmacologica Sinica · 2025Article
- Optochemical profiling of NMDAR molecular diversity at synaptic and extrasynaptic sites.The EMBO journal · 2025Article
- Regulation of NMDAR activation efficiency by environmental factors and subunit composition.The Journal of general physiology · 2025Article
- Structural basis for antibody-mediated NMDA receptor clustering and endocytosis in autoimmune encephalitis.Nature structural & molecular biology · 2024Article
- 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
- 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
- Complex functional phenotypes of NMDA receptor disease variants.Molecular psychiatry · 2022Article
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- GluN2A and GluN2B NMDA receptors use distinct allosteric routes.Nature communications · 2021Article
- Correlated conformational dynamics of the human GluN1-GluN2A type N-methyl-D-aspartate (NMDA) receptor.Journal of molecular modeling · 2021Article
- NMDA Receptors Require Multiple Pre-opening Gating Steps for Efficient Synaptic Activity.Neuron · 2021Article
- From bedside-to-bench: What disease-associated variants are teaching us about the NMDA receptor.The Journal of physiology · 2021Review
- Hodgkin-Huxley-Katz Prize Lecture: Genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif.The Journal of physiology · 2020Article
- NMDA receptor channel gating control by the pre-M1 helix.The Journal of general physiology · 2020Article
- Biased modulators of NMDA receptors control channel opening and ion selectivity.Nature chemical biology · 2020Article
- Prying open a glutamate receptor gate.The Journal of general physiology · 2019Article
- Noncompetitive antagonists induce cooperative AMPA receptor channel gating.The Journal of general physiology · 2019Article
- An inter-dimer allosteric switch controls NMDA receptor activity.The EMBO journal · 2019Article
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3 authors at 2 institutions in 1 country.
Funding
Abstract
Gating in the NMDA receptor is initiated in the extracellular ligand-binding domain (LBD) and is ultimately propagated via three linkers-S1-M1, M3-S2, and S2-M4-to the ion channel. M3-S2 directly couples LBD movements into channel gating, but the functional and structural contributions of S1-M1 and S2-M4 to the overall gating process are unknown. A scan of substituted cysteines in and around the NMDA receptor S1-M1 and S2-M4 with a bulky cysteine-reactive reagent identified numerous positions that showed potentiation of glutamate-activated as well as leak currents. As indexed by MK801 (dizocilpine hydrogen maleate), an open channel blocker, this potentiation was attributable to an increase in open probability, an interpretation confirmed for a subset of positions with single-channel recordings. The magnitude of this gating effect, acting through S1-M1 or S2-M4, was dependent on the intrinsic gating properties of the NMDA receptors, being more effective in the inherently low open probability GluN2C- than the higher open probability GluN2A-subunit-containing receptors. For the majority of these potentiation positions, we propose that alteration of gating arises from steric destabilization of contact interfaces where close apposition of the contacting partners is necessary for efficient channel closure. Our results therefore indicate that the NMDA receptor S1-M1 and S2-M4 linkers are dynamic during gating and can modulate the overall energetics of this process. Furthermore, the results conceptualize a mechanistic, as well as a possible structural, framework for pharmacologically targeting the linkers through noncompetitive and subunit-specific modes of action.
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