2017
DOI: 10.1038/nchembio.2487
|View full text |Cite
|
Sign up to set email alerts
|

The structure–energy landscape of NMDA receptor gating

Abstract: N-methyl-D-aspartate (NMDA) receptors are the main calcium-permeable excitatory receptors in the mammalian central nervous system. The NMDA receptor gating is complex, exhibiting multiple closed, open, and desensitized states; however, the central questions regarding the conformations and energetics of the transmembrane domains as they relate to the gating states are still unanswered. Here, using single molecule Förster Resonance Energy Transfer (smFRET), we map the energy landscape of the first transmembrane … Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
1
1
1
1

Citation Types

6
61
0

Year Published

2018
2018
2024
2024

Publication Types

Select...
5
3

Relationship

1
7

Authors

Journals

citations
Cited by 47 publications
(67 citation statements)
references
References 54 publications
6
61
0
Order By: Relevance
“…In addition to rendering channels impermeable, the blocker changed transition rates in the activation sequence, indicative of a trapping block mechanism. This kinetic model identified blocker-sensitive transition rates, blocker concentration-dependence of receptor open probability, and stimulus-dependence of blocker efficacy thus supporting the premise that in addition to occluding permeation this ligand also alters activation kinetics [17 • ]. Delineating blocker mechanisms with similar detail will be necessary to understand why different blockers affect NMDA receptor responses differentially, a vexing unanswered question.…”
Section: Modifying the Nmda Receptor Response With Modulators And Blomentioning
confidence: 62%
See 1 more Smart Citation
“…In addition to rendering channels impermeable, the blocker changed transition rates in the activation sequence, indicative of a trapping block mechanism. This kinetic model identified blocker-sensitive transition rates, blocker concentration-dependence of receptor open probability, and stimulus-dependence of blocker efficacy thus supporting the premise that in addition to occluding permeation this ligand also alters activation kinetics [17 • ]. Delineating blocker mechanisms with similar detail will be necessary to understand why different blockers affect NMDA receptor responses differentially, a vexing unanswered question.…”
Section: Modifying the Nmda Receptor Response With Modulators And Blomentioning
confidence: 62%
“…This linear activation sequence depicts the most rapid pathway by which resting receptors can open (activation) and open receptors can deactivate (deactivation). Recently, single-molecule FRET data have supported this linear arrangement of states [17 • ]. Its transition rates set the rise and decay timecourse for synaptic NMDA receptor currents (Figure 1b) and the decay timecourse of the excitatory postsynaptic current (EPSC).…”
Section: Activation Of Nmda Receptor Subtypesmentioning
confidence: 79%
“…Here we show how the GluN1/GluN2A receptor populates an ensemble of structural states depending on zinc and proton concentrations (Amico-Ruvio et al, 2011; Dolino et al, 2017; Erreger and Traynelis, 2008). The 1-knuckle conformation, one of the structural conformations that the receptor adopts when inhibited by zinc and protons, resembles the GluN1/GluN2B receptor bound by ifenprodil or Ro25–6891 (Tajima et al, 2016; Zhu et al, 2016).…”
Section: Resultsmentioning
confidence: 97%
“…Consistent with zinc and ifenprodil inhibiting NMDARs through similar structural mechanisms, ifenprodil enhances zinc and proton sensitivity (Amico-Ruvio et al, 2012; Mott et al, 1998; Pahk and Williams, 1997) and zinc enhances ifenprodil sensitivity and the extent of inhibition (Hansen et al, 2014). Indeed, single molecule studies support an ensemble of electrophysiologically silent states, where the NMDA receptor populates pre-open or low P O states in the presence of zinc (Amico-Ruvio et al, 2011; Christine and Choi, 1990; Dolino et al, 2017; Erreger and Traynelis, 2008). …”
Section: Introductionmentioning
confidence: 99%
“…In studies examining how the NTD‐binding allosteric inhibitors zinc and ifenprodil affect the gating reaction of NMDARs, the same pre‐open to open transition is preferentially affected (Amico‐Ruvio et al , , ). Single‐molecule FRET analysis also indicates that zinc inhibition of NMDARs occurs by uncoupling of the agonist‐induced changes at the ABD domains from the gating motions (Dolino et al , ). Our work provides the novel information that this uncoupling occurs through a quaternary rearrangement involving the unrolling of the two constitutive ABD dimers.…”
Section: Discussionmentioning
confidence: 99%