ArticleNeuron2021
NMDA Receptors Require Multiple Pre-opening Gating Steps for Efficient Synaptic Activity.
Article in Neuron, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- Structural and mechanistic insights into gating and allosteric modulation of GluN1-GluN3A NMDA receptors.Nature structural & molecular biology · 2026Article
- Article
- Gene Therapy Approaches for Atherosclerosis Focusing on Targeting Lipid Metabolism and Inflammation.International journal of molecular sciences · 2025Review
- Membrane Association of Intrinsically Disordered Proteins.Annual review of biophysics · 2025Review
- Regulation of NMDAR activation efficiency by environmental factors and subunit composition.The Journal of general physiology · 2025Article
- Subtype-specific conformational landscape of NMDA receptor gating.Cell reports · 2024Article
- Developmental loss of NMDA receptors results in supernumerary forebrain neurons through delayed maturation of transit-amplifying neuroblasts.Scientific reports · 2024Article
- Calcium- and calmodulin-dependent inhibition of NMDA receptor currents.Biophysical journal · 2024Review
- 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
- Complex functional phenotypes of NMDA receptor disease variants.Molecular psychiatry · 2022Article
- Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor.Nature communications · 2022Article
- Effects of Dexmedetomidine and Oxycodone on Neurocognitive and Inflammatory Response After Tourniquet-Induced Ischemia-Reperfusion Injury.Neurochemical research · 2022Article
- Protein quality control ofFrontiers in cellular neuroscience · 2022Review
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- GluN2A and GluN2B NMDA receptors use distinct allosteric routes.Nature communications · 2021Article
- The Negative Allosteric Modulator EU1794-4 Reduces Single-Channel Conductance and CaMolecular pharmacology · 2021Article
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5 authors at 1 institution in 1 country.
Funding
Abstract
NMDA receptors (NMDARs) are glutamate-gated ion channels that mediate fast excitatory synaptic transmission in the nervous system. Applying glutamate to outside-out patches containing a single NMDAR, we find that agonist-bound receptors transition to the open state via two conformations, an "unconstrained pre-active" state that contributes to fast synaptic events and a "constrained pre-active" state that does not. To define how glutamate drives these conformations, we decoupled the ligand-binding domains from specific transmembrane segments for GluN1 and GluN2A. Displacements of the pore-forming M3 segments define the energy of fast opening. However, to enter the unconstrained conformation and contribute to fast signaling, the GluN2 pre-M1 helix must be displaced before the M3 segments move. This pre-M1 displacement is facilitated by the flexibility of the S2-M4 of GluN1 and GluN2A. Thus, outer structures-pre-M1 and S2-M4-work in concert to remove constraints and prime the channel for rapid opening, facilitating fast synaptic transmission.
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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.