ArticleMolecular pharmacology2013
Contribution of the M1 transmembrane helix and pre-M1 region to positive allosteric modulation and gating of N-methyl-D-aspartate receptors.
Article in Molecular pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 54 citations in OpenAlex.
- Discovery of selective GluN1/GluN3A NMDA receptor inhibitors using integrated AI and physics-based approaches.Acta pharmacologica Sinica · 2026Article
- New advances in small molecule drugs targeting NMDA receptors.Acta pharmacologica Sinica · 2026Review
- Discovery of novel GluN1/GluN3A NMDA receptor inhibitors using a deep learning-based method.Acta pharmacologica Sinica · 2025Article
- Activation of GluN2D-containing NMDA receptors promotes development of axons and axon-carrying dendrites of cortical interneurons.Cerebral cortex (New York, N.Y. : 1991) · 2025Article
- Structural insights into NMDA receptor pharmacology.Biochemical Society transactions · 2023Review
- 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
- N-methyl-D-aspartate receptor hypofunction as a potential contributor to the progression and manifestation of many neurological disorders.Frontiers in molecular neuroscience · 2023Review
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- 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
- Distinct GluN1 and GluN2 Structural Determinants for Subunit-Selective Positive Allosteric Modulation ofACS chemical neuroscience · 2021Article
- From bedside-to-bench: What disease-associated variants are teaching us about the NMDA receptor.The Journal of physiology · 2021Review
- Negative allosteric modulation of GluN1/GluN3 NMDA receptors.Neuropharmacology · 2020Article
- 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
- Differential effect of NMDA receptor GluN2C and GluN2D subunit ablation on behavior and channel blocker-induced schizophrenia phenotypes.Scientific reports · 2019Article
- An inter-dimer allosteric switch controls NMDA receptor activity.The EMBO journal · 2019Article
- Positive and Negative Allosteric Modulators of N-Methyl-d-aspartate (NMDA) Receptors: Structure-Activity Relationships and Mechanisms of Action.Journal of medicinal chemistry · 2019Review
- The NMDA receptor intracellular C-terminal domains reciprocally interact with allosteric modulators.Biochemical pharmacology · 2019Article
- A structurally derived model of subunit-dependent NMDA receptor function.The Journal of physiology · 2018Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
N-methyl-D-aspartate (NMDA) receptors are glutamate-gated ion channels whose function is critical for normal excitatory synaptic transmission in the brain and whose dysfunction has been implicated in several neurologic conditions. NMDA receptor function is subject to extensive allosteric regulation both by endogenous compounds and by exogenous small molecules. Elucidating the structural determinants and mechanism of action by which allosteric regulators control gating will enhance our understanding of NMDA receptor activation and facilitate the development of novel therapeutics. Here, we investigated the structural determinants for (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ), a GluN2C/2D-selective positive allosteric modulator. We show that CIQ does not bind to the amino-terminal domain of the NMDA receptor and does not share structural determinants with modulators acting at the agonist-binding domain dimer interface or ion channel pore. Rather, we identified critical determinants of CIQ modulation in the region near the first transmembrane helix of GluN2D, including in a putative pre-M1 cuff helix that may influence channel gating. We also show that mutations within the GluN2D pre-M1 region alter open probability of the NMDA receptor. These results suggest a novel site of action for potentiation of NMDA receptors by small molecules and implicate the pre-M1 region in NMDA receptor gating.
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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.