ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2005
AMPA receptor binding cleft mutations that alter affinity, efficacy, and recovery from desensitization.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 113 citations in OpenAlex.
- Kainate Receptors in Sensory Neurons: Molecular Identity and Functional Relevance to Pain.Neuroscience bulletin · 2026Review
- Structures of partially occupied hetero-tetramers provide insight into kainate receptor activation and desensitization.Nature communications · 2026Article
- Modeling the use of transient ligand binding information by AMPA receptors.NPJ systems biology and applications · 2025Article
- Subtype-specific conformational landscape of NMDA receptor gating.Cell reports · 2024Article
- Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor.Nature communications · 2022Article
- Structural Dynamics of Glutamate Signaling Systems by smFRET.Biophysical journal · 2020Review
- TARPs Modulate Receptor-Mediated Paired-Pulse Depression and Recovery from Desensitization.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Subunit-selective iGluR antagonists can potentiate heteromeric receptor responses by blocking desensitization.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Measurements of the Timescale and Conformational Space of AMPA Receptor Desensitization.Biophysical journal · 2020Article
- The Route to 'Chemobrain' - Computational probing of neuronal LTP pathway.Scientific reports · 2019Article
- Mapping the Conformational Landscape of Glutamate Receptors Using Single Molecule FRET.Trends in neurosciences · 2019Review
- Population Shift Mechanism for Partial Agonism of AMPA Receptor.Biophysical journal · 2019Article
- Article
- Unitary Properties of AMPA Receptors with Reduced Desensitization.Biophysical journal · 2017Article
- Article
- Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating.Scientific reports · 2017Article
- Mechanism of partial agonism in AMPA-type glutamate receptors.Nature communications · 2017Article
- Molecular lock regulates binding of glycine to a primitive NMDA receptor.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Structural mechanisms of activation and desensitization in neurotransmitter-gated ion channels.Nature structural & molecular biology · 2016Review
- Acid-sensing ion channels are tuned to follow high-frequency stimuli.The Journal of physiology · 2016Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glutamate binds to AMPA receptors within a deep cleft between two globular protein domains (domains 1 and 2). Once glutamate binds, the cleft closes, and agonist-bound structures of the isolated ligand binding core suggest that closure of the binding cleft is sufficiently complete that it essentially prevents ligand dissociation. There is also considerable evidence supporting the view that cleft closure is the initial conformational change that triggers receptor activation and desensitization, and it has been clearly demonstrated that there is a correlation between the degree of cleft closure and agonist efficacy. It is unknown, however, whether the stability of binding cleft closure also influences receptor-channel properties. The crystallographic structures indicate that closed-cleft conformations are stabilized by the formation of hydrogen bonds that involve amino acid side chains of residues in domains 1 and 2. We show here that mutations that disrupt one such cross-cleft hydrogen bond (in the AMPA receptor subunit GluR2) decrease both agonist affinity and efficacy. The same mutations also hasten recovery from desensitization. We conclude that the stability of binding cleft closure has a significant impact on AMPA receptor function and is a major determinant of the apparent affinity of agonists. The results suggest that the stability of cleft closure has been tuned so that glutamate dissociates as rapidly as possible yet remains a full agonist.
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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.