ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2009
Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 152 papers.
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Who cites it
152 citing papers in PubMed, 261 citations in OpenAlex.
- Ketamine induces multiple individually distinct whole-brain functional connectivity signatures.eLife · 2024Trial
- NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia.Proceedings of the National Academy of Sciences of the United States of America · 2012Trial
- GluN2D NMDA Receptors: Bridging Physiology and Pathology.Biological psychiatry · 2026Review
- Memantine: updates from the past decade and implications for future novel therapeutic applications.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- N-Methyl-D-aspartate receptors: structure, signaling and roles in atherosclerosis.Journal of translational medicine · 2026Review
- State-specific inhibition of NMDA receptors by memantine provides insight into NMDAR channel blocker tolerability.Science advances · 2026Article
- Inhibition of GluN2B-containing N-methyl-D-aspartate receptors by radiprodil.Brain : a journal of neurology · 2026Article
- Targeting NMDA receptors in pain management: therapeutic innovations through piracetam repurposing.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- Bioisostere-Driven Discovery of SePP: A Selenium-Containing Polypharmacological Agent Relevant to Fragile X Syndrome.Journal of medicinal chemistry · 2026Article
- Esketamine/Ketamine: Dual-Action Mechanisms and Clinical Prospects beyond Anesthesia in Psychiatry, Immunology, and Oncology.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- A mouse model of GRIN2D developmental and epileptic encephalopathy recapitulates the human disease.Brain : a journal of neurology · 2026Article
- Automated ROI detection allows rapid quantification of synaptic activity across tens of thousands of synapses in cell culture.Frontiers in synaptic neuroscience · 2026Article
- The NMDA receptor subunit GluN2D is a potential target for rapid antidepressant action.Nature communications · 2025Article
- Computational modeling of ketamine-induced changes in gamma-band oscillations: The contribution of parvalbumin and somatostatin interneurons.PLoS computational biology · 2025Article
- Structural basis for channel gating and blockade in tri-heteromeric GluN1-2B-2D NMDA receptor.Neuron · 2025Article
- An antidepressant mechanism underlying the allosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons.Science advances · 2025Article
- Allosteric inhibition of NMDA receptors by low dose ketamine.Molecular psychiatry · 2025Article
- GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain.Neurobiology of disease · 2025Article
- EAR-20 peptide, a novel NMDA receptor positive allosteric modulator.Frontiers in pharmacology · 2025Article
- Contrasting patterns of extrasynaptic NMDAR-GluN2B expression in macaque subgenual cingulate and dorsolateral prefrontal cortices.Frontiers in neuroanatomy · 2025Article
92 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
N-methyl-D-aspartate receptors (NMDARs) mediate interneuronal communication and are broadly involved in nervous system physiology and pathology (Dingledine et al., 1999). Memantine, a drug that blocks the ion channel formed by NMDARs, is a widely prescribed treatment of Alzheimer's disease (Schmitt, 2005; Lipton, 2006; Parsons et al., 2007). Research on memantine's mechanism of action has focused on the NMDAR subtypes most highly expressed in adult cerebral cortex, NR1/2A and NR1/2B receptors (Cull-Candy and Leszkiewicz, 2004), and has largely ignored interactions with extracellular Mg(2+) (Mg(2+)(o)). Mg(2+)(o) is an endogenous NMDAR channel blocker that binds near memantine's binding site (Kashiwagi et al., 2002; Chen and Lipton, 2005). We report that a physiological concentration (1 mM) of Mg(2+)(o) decreased memantine inhibition of NR1/2A and NR1/2B receptors nearly 20-fold at a membrane voltage near rest. In contrast, memantine inhibition of the other principal NMDAR subtypes, NR1/2C and NR1/2D receptors, was decreased only approximately 3-fold. As a result, therapeutic memantine concentrations should have negligible effects on NR1/2A or NR1/2B receptor activity but pronounced effects on NR1/2C and NR1/2D receptors. Quantitative modeling showed that the voltage dependence of memantine inhibition also is altered by 1 mM Mg(2+)(o). We report similar results with the NMDAR channel blocker ketamine, a drug used to model schizophrenia (Krystal et al., 2003). These results suggest that currently hypothesized mechanisms of memantine and ketamine action should be reconsidered and that NR1/2C and/or NR1/2D receptors play a more important role in cortical physiology and pathology than previously appreciated.
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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.