ArticleProceedings of the National Academy of Sciences of the United States of America2005
Structural determinants of agonist-specific kinetics at the ionotropic glutamate receptor 2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 32 citations in OpenAlex.
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- 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
- Estimation of ligand efficacies of metabotropic glutamate receptors from conformational forces obtained from molecular dynamics simulations.Journal of chemical information and modeling · 2013Article
- The biology of the glutamatergic system and potential role in migraine.International journal of biomedical science : IJBS · 2013Article
- Article
- Size matters in activation/inhibition of ligand-gated ion channels.Trends in pharmacological sciences · 2012Review
- Atomistic mechanism for the activation and desensitization of an AMPA-subtype glutamate receptor.Nature communications · 2011Article
- The hidden energetics of ligand binding and activation in a glutamate receptor.Nature structural & molecular biology · 2011Article
- NMDA receptors with locked glutamate-binding clefts open with high efficacy.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2010Article
- Glutamate receptor ion channels: structure, regulation, and function.Pharmacological reviews · 2010Review
- On the mechanisms of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor binding to glutamate and kainate.The Journal of biological chemistry · 2010Article
- Energy transfer ligands of the GluR2 ligand binding core.Biochemistry · 2010Article
- The free energy landscapes governing conformational changes in a glutamate receptor ligand-binding domain.Structure (London, England : 1993) · 2007Article
- Pharmacological insights obtained from structure-function studies of ionotropic glutamate receptors.British journal of pharmacology · 2006Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glutamate receptors (GluRs) are the most abundant mediators of the fast excitatory neurotransmission in the human brain. Agonists will, after activation of the receptors, induce different degrees of desensitization. The efficacy of agonists strongly correlates with the agonist-induced closure of the ligand-binding domain. However, the differences in desensitization properties are less well understood. By using high-resolution x-ray structure of the GluR2 flop (GluR2o) ligand-binding core protein in complex with the partial glutamate receptor agonist (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isothiazolyl)propionic acid [(S)-thio-ATPA], we show that (S)-thio-ATPA induces an 18 degrees closure of the binding core similar to another partial agonist, (S)-2-amino-3-(4-bromo-3-hydroxy-5-isoxazolyl)propionic acid [(S)-Br-HIBO]. Despite the similar closure of the ligand-binding domain, we find in electrophysiological studies that (S)-thio-ATPA induced a 6.4-fold larger steady-state current than (RS)-Br-HIBO, and rapid agonist applications show that (S)-thio-ATPA induces a 3.6-fold higher steady-state/peak ratio and a 2.2-fold slower desensitization time constant than (RS)-Br-HIBO. Structural comparisons reveal that (S)-Br-HIBO, but not (S)-thio-ATPA, induces a twist of the ligand-binding core compared with the apostructure, and the agonist-specific conformation of Leu-650 correlates with the different kinetic profiles pointing at a key role in defining the desensitization kinetics. We conclude that, especially for intermediate efficacious agonists, the desensitization properties are influenced by additional ligand-induced factors beyond domain closure.
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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.