ArticleThe Journal of general physiology2011
Local constraints in either the GluN1 or GluN2 subunit equally impair NMDA receptor pore opening.
Article in The Journal of general physiology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 50 citations in OpenAlex.
- Subconductance states in NMDA receptor variants are CaResearch square · 2026Article
- Calcium- and calmodulin-dependent inhibition of NMDA receptor currents.Biophysical journal · 2024Review
- Two gates mediate NMDA receptor activity and are under subunit-specific regulation.Nature communications · 2023Article
- A heterozygous GRID2 mutation in autosomal dominant cerebellar ataxia.Human genome variation · 2022Article
- NMDA Receptors Require Multiple Pre-opening Gating Steps for Efficient Synaptic Activity.Neuron · 2021Article
- 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
- Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory.Nature communications · 2020Article
- A conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high CaNature communications · 2018Article
- A structurally derived model of subunit-dependent NMDA receptor function.The Journal of physiology · 2018Article
- A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors.Scientific reports · 2017Article
- Divergent roles of a peripheral transmembrane segment in AMPA and NMDA receptors.The Journal of general physiology · 2017Article
- Functional Evaluation of a De NovoMolecular pharmacology · 2017Article
- Advancing NMDA Receptor Physiology by Integrating Multiple Approaches.Trends in neurosciences · 2017Review
- Disruption of S2-M4 linker coupling reveals novel subunit-specific contributions to N-methyl-d-aspartate receptor function and ethanol sensitivity.Neuropharmacology · 2016Article
- Bidirectional Effect of Pregnenolone Sulfate on GluN1/GluN2A N-Methyl-D-Aspartate Receptor Gating Depending on Extracellular Calcium and Intracellular Milieu.Molecular pharmacology · 2015Article
- Structure, Dynamics, and Allosteric Potential of Ionotropic Glutamate Receptor N-Terminal Domains.Biophysical journal · 2015Review
- Mechanism-Based Mathematical Model for Gating of Ionotropic Glutamate Receptors.The journal of physical chemistry. B · 2015Article
- Subtype-dependent N-methyl-D-aspartate receptor amino-terminal domain conformations and modulation by spermine.The Journal of biological chemistry · 2015Article
- Cysteine substitution of transmembrane domain amino acids alters the ethanol inhibition of GluN1/GluN2A N-methyl-D-aspartate receptors.The Journal of pharmacology and experimental therapeutics · 2015Article
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
The defining functional feature of N-methyl-d-aspartate (NMDA) receptors is activation gating, the energetic coupling of ligand binding into opening of the associated ion channel pore. NMDA receptors are obligate heterotetramers typically composed of glycine-binding GluN1 and glutamate-binding GluN2 subunits that gate in a concerted fashion, requiring all four ligands to bind for subsequent opening of the channel pore. In an individual subunit, the extracellular ligand-binding domain, composed of discontinuous polypeptide segments S1 and S2, and the transmembrane channel-forming domain, composed of M1-M4 segments, are connected by three linkers: S1-M1, M3-S2, and S2-M4. To study subunit-specific events during pore opening in NMDA receptors, we impaired activation gating via intrasubunit disulfide bonds connecting the M3-S2 and S2-M4 in either the GluN1 or GluN2A subunit, thereby interfering with the movement of the M3 segment, the major pore-lining and channel-gating element. NMDA receptors with gating impairments in either the GluN1 or GluN2A subunit were dramatically resistant to channel opening, but when they did open, they showed only a single-conductance level indistinguishable from wild type. Importantly, the late gating steps comprising pore opening to its main long-duration open state were equivalently affected regardless of which subunit was constrained. Thus, the NMDA receptor ion channel undergoes a pore-opening mechanism in which the intrasubunit conformational dynamics at the level of the ligand-binding/transmembrane domain (TMD) linkers are tightly coupled across the four subunits. Our results further indicate that conformational freedom of the linkers between the ligand-binding and TMDs is critical to the activation gating process.
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