ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2008
The activation gate and gating mechanism of the NMDA receptor.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008. 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, 89 citations in OpenAlex.
- Pre-activation and gating pathway of AMPA receptors revealed by full and partial agonists.Nature structural & molecular biology · 2026Article
- NMDA Receptors in Neurodevelopmental Disorders: Pathophysiology and Disease Models.International journal of molecular sciences · 2024Review
- Structural insights into NMDA receptor pharmacology.Biochemical Society transactions · 2023Review
- Two gates mediate NMDA receptor activity and are under subunit-specific regulation.Nature communications · 2023Article
- Pulsed Radiofrequency Decreases pERK and Affects Intracellular CaJournal of pain research · 2023Article
- Structural basis of AMPA receptor inhibition by trans-4-butylcyclohexane carboxylic acid.British journal of pharmacology · 2022Article
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- Recurrent seizure-related GRIN1 variant: Molecular mechanism and targeted therapy.Annals of clinical and translational neurology · 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
- Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors.Proceedings of the National Academy of Sciences of the United States of America · 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
- Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions.The Journal of general physiology · 2020Article
- NMDA receptor channel gating control by the pre-M1 helix.The Journal of general physiology · 2020Article
- Extremely low frequency magnetic field induces human neuronal differentiation through NMDA receptor activation.Journal of neural transmission (Vienna, Austria : 1996) · 2019Article
- Cadmium opens GluK2 kainate receptors with cysteine substitutions at the M3 helix bundle crossing.The Journal of general physiology · 2019Article
- Prying open a glutamate receptor gate.The Journal of general physiology · 2019Article
- Coupling of a viral KCommunications biology · 2019Article
- Structure, function, and allosteric modulation of NMDA receptors.The Journal of general physiology · 2018Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The NMDA receptor opens in response to binding of NMDA and glycine. However, it remains unclear where and how gating of the NMDA receptor pore is accomplished. We show that different point mutations between S645 and I655 (thus including the highly conserved SYTANLAAF motif) of M3c in NR2B lead to constitutively open channels. The current through these constitutively open channels are readily blocked by external Mg2+ and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]. Also, the open-channel blocker MK-801 can no longer be trapped in these channels when NMDA and glycine are washed off. Moreover, M3c residues at or below A651(NR2B, A7 in SYTANLAAF) react with external methanethiosulfonate (MTS) reagents approximately 500 to 1000-fold faster in the presence than in the absence of agonists NMDA and glycine. In fact, the MTS modification rate shows exactly the same NMDA concentration dependence as channel activation. In contrast, those residues external to A651 are always modified with similar kinetics whether NMDA and glycine are present or not. Interestingly, MTS modification of A651C(NR2B) holds the channel constitutively open. Mutations of A651(NR2B) into arginine, tryptophan, or phenylalanine, and similar mutations of the corresponding A652 in NR1 also lead to constitutively open channels. Double-mutant cycle analysis further shows that the effects of A652(NR1) and A651(NR2B) mutations are evidently non-additive (i.e., cooperative) if mutated into residues with large side chains or with compensatory charges [e.g., A652E(NR1)+A651R(NR2B)]. The side chain of A7 thus plays a determinant role in the intersubunit distance at this level, which is directly responsible for the activation gate and activation-deactivation gating of the NMDA receptor.
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