ArticleThe Journal of general physiology2012
Probing the activation sequence of NMDA receptors with lurcher mutations.
Article in The Journal of general physiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Context-dependent NMDA receptor dysfunction predicts seizure treatment in mice with human GluN1 variant.iScience · 2026Article
- Loss of activation by GABA in vertebrate delta ionotropic glutamate receptors.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- 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
- Protein quality control ofFrontiers in cellular neuroscience · 2022Review
- 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
- Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions.The Journal of general physiology · 2020Article
- Cadmium opens GluK2 kainate receptors with cysteine substitutions at the M3 helix bundle crossing.The Journal of general physiology · 2019Article
- Noncompetitive antagonists induce cooperative AMPA receptor channel gating.The Journal of general physiology · 2019Article
- Article
- De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.Brain : a journal of neurology · 2018Article
- Resident Calmodulin Primes NMDA Receptors for CaBiophysical journal · 2017Article
- A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors.Scientific reports · 2017Article
- Probing the Structural Dynamics of the NMDA Receptor Activation by Coarse-Grained Modeling.Biophysical journal · 2017Article
- Advancing NMDA Receptor Physiology by Integrating Multiple Approaches.Trends in neurosciences · 2017Review
- All atom NMDA receptor transmembrane domain model development and simulations in lipid bilayers and water.PloS one · 2017Article
- Modulation of NMDA channel gating by CaScientific reports · 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
- The differential contribution of GluN1 and GluN2 to the gating operation of the NMDA receptor channel.Pflugers Archiv : European journal of physiology · 2015Article
- Block of NMDA receptor channels by endogenous neurosteroids: implications for the agonist induced conformational states of the channel vestibule.Scientific reports · 2015Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
N-methyl-D-aspartate (NMDA) receptor activation involves a dynamic series of structural rearrangements initiated by glutamate binding to glycine-loaded receptors and culminates with the clearing of the permeation pathway, which allows ionic flux. Along this sequence, three rate-limiting transitions can be quantified with kinetic analyses of single-channel currents, even though the structural determinants of these critical steps are unknown. In inactive receptors, the major permeation barrier resides at the intersection of four M3 transmembrane helices, two from each GluN1 and GluN2 subunits, at the level of the invariant SYTANLAAF sequence, known as the lurcher motif. Because the A7 but not A8 residues in this region display agonist-dependent accessibility to extracellular solutes, they were hypothesized to form the glutamate-sensitive gate. We tested this premise by examining the reaction mechanisms of receptors with substitutions in the lurcher motifs of GluN1 or GluN2A subunits. We found that, consistent with their locations relative to the proposed activation gate, A8Y decreased open-state stability, whereas A7Y dramatically stabilized open states, primarily by preventing gate closure; the equilibrium distribution of A7Y receptors was strongly shifted toward active states and resulted in slower microscopic association and dissociation rate constants for glutamate. In addition, for both A8- and A7-substituted receptors, we noticed patterns of kinetic changes that were specific to GluN1 or GluN2 locations. This may be a first indication that the sequence of discernible kinetic transitions during NMDA receptor activation may reflect subunit-dependent movements of M3 helices. Testing this hypothesis may afford insight into the activation mechanism of NMDA receptors.
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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.