ArticleThe Journal of physiology2007
Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block.
Article in The Journal of physiology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers.
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Who cites it
94 citing papers in PubMed, 177 citations in OpenAlex.
- Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects.Molecular psychiatry · 2014Trial
- GluN2D NMDA Receptors: Bridging Physiology and Pathology.Biological psychiatry · 2026Review
- N-Methyl-D-aspartate receptors: structure, signaling and roles in atherosclerosis.Journal of translational medicine · 2026Review
- Combined Inhibition of TRPM4/NMDA Receptor Complex and Extrasynaptic NMDA Receptors Is Candidate Therapeutic Target for Suppression of Epileptic Seizures and Improvement of Cognitive Impairments.Pharmacology research & perspectives · 2026Article
- State-specific inhibition of NMDA receptors by memantine provides insight into NMDAR channel blocker tolerability.Science advances · 2026Article
- A mouse model of GRIN2D developmental and epileptic encephalopathy recapitulates the human disease.Brain : a journal of neurology · 2026Article
- New advances in small molecule drugs targeting NMDA receptors.Acta pharmacologica Sinica · 2026Review
- Effects of NMDA receptor antagonists on working memory and gamma oscillations, and the mediating role of the GluN2D subunit.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Ketogenic diet for infantile epileptic spasms.Epilepsia open · 2025Article
- Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?The American journal of psychiatry · 2025Review
- Allosteric inhibition of NMDA receptors by low dose ketamine.Molecular psychiatry · 2025Article
- Regulation of NMDAR activation efficiency by environmental factors and subunit composition.The Journal of general physiology · 2025Article
- KETAMIR-2, a new molecular entity and novel ketamine analog.Frontiers in pharmacology · 2025Article
- Article
- Effects of Sarcosine (N-methylglycine) on NMDA (N-methyl-D-aspartate) Receptor Hypofunction Induced by MK801: In Vivo Calcium Imaging in the CA1 Region of the Dorsal Hippocampus.Brain sciences · 2024Article
- Ketamine's Amelioration of Fear Extinction in Adolescent Male Mice Is Associated with the Activation of the Hippocampal Akt-mTOR-GluA1 Pathway.Pharmaceuticals (Basel, Switzerland) · 2024Article
- The role of NMDARs in the anesthetic and antidepressant effects of ketamine.CNS neuroscience & therapeutics · 2024Review
- Targeting metaplasticity mechanisms to promote sustained antidepressant actions.Molecular psychiatry · 2024Review
- Clinical features, functional consequences, and rescue pharmacology of missense GRID1 and GRID2 human variants.Human molecular genetics · 2024Article
- MK-801 and cognitive functions: Investigating the behavioral effects of a non-competitive NMDA receptor antagonist.Psychopharmacology · 2023Review
34 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
We have compared the potencies of structurally distinct channel blockers at recombinant NR1/NR2A, NR1/NR2B, NR1/NR2C and NR1/NR2D receptors. The IC50 values varied with stereochemistry and subunit composition, suggesting that it may be possible to design subunit-selective channel blockers. For dizocilpine (MK-801), the differential potency of MK-801 stereoisomers determined at recombinant NMDA receptors was confirmed at native receptors in vitro and in vivo. Since the proton sensor is tightly linked both structurally and functionally to channel gating, we examined whether blocking molecules that interact in the channel pore with the gating machinery can differentially sense protonation of the receptor. Blockers capable of remaining trapped in the pore during agonist unbinding showed the strongest dependence on extracellular pH, appearing more potent at acidic pH values that promote channel closure. Determination of pK(a) values for channel blockers suggests that the ionization of ketamine but not of other blockers can influence its pH-dependent potency. Kinetic modelling and single channel studies suggest that the pH-dependent block of NR1/NR2A by (-)MK-801 but not (+)MK-801 reflects an increase in the MK-801 association rate even though protons reduce channel open probability and thus MK-801 access to its binding site. Allosteric modulators that alter pH sensitivity alter the potency of MK-801, supporting the interpretation that the pH sensitivity of MK-801 binding reflects the changes at the proton sensor rather than a secondary effect of pH. These data suggest a tight coupling between the proton sensor and the ion channel gate as well as unique subunit-specific mechanisms of channel block.
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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.