Functional Insights from Glutamate Receptor Ion Channel Structures

Kumar, Janesh; Mayer, Mark L.

doi:10.1146/annurev-physiol-030212-183711

Cited by 126 publications

(126 citation statements)

References 143 publications

(176 reference statements)

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“…The results from our initial screening provide some initial insight into the structure-activity relationship that might be of value for future efforts to improve potency. For example, agonist activity at iGluRs in general requires the LBD to adopt a conformation in which the D1 and D2 lobes are near-fully or fully closed around the ligand (Pohlsgaard et al, 2011;Kumar and Mayer, 2013). This may pose specific limits for the size of the agonist structure that depend on the volume of the ligand binding cavity.…”

Section: Discussionmentioning

confidence: 99%

Pharmacology and Structural Analysis of Ligand Binding to the Orthosteric Site of Glutamate-Like GluD2 Receptors

et al. 2015

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The GluD2 receptor is a fundamental component of postsynaptic sites in Purkinje neurons, and is required for normal cerebellar function. GluD2 and the closely related GluD1 are classified as members of the ionotropic glutamate receptor (iGluR) superfamily on the basis of sequence similarity, but do not bind L-glutamate. The amino acid neurotransmitter D-Ser is a GluD2 receptor ligand, and endogenous D-Ser signaling through GluD2 has recently been shown to regulate endocytosis of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type iGluRs during synaptic plasticity in the cerebellum, such as long-term depression. Here, we investigate the pharmacology of the orthosteric binding site in GluD2 by examining the activity of analogs of D-Ser and GluN1 glycine site competitive antagonists at GluD2

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Section: Discussionmentioning

confidence: 99%

Pharmacology and Structural Analysis of Ligand Binding to the Orthosteric Site of Glutamate-Like GluD2 Receptors

et al. 2015

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“…1 A). Binding of agonists (glutamate and glycine) to the extracellular ligand-binding domains (LBDs) results in currents through the transmembrane channel (1,2). Within each iGluR subunit, the LBD is connected to the transmembrane domain by three flexible linkers (3,4).…”

Section: Introductionmentioning

confidence: 99%

“…Because of their critical functions and their association with numerous diseases (1,2,5), iGluRs have been intensively studied from multiple angles, including electrophysiology, structural characterization, computation, and mathematical modeling. A number of studies have attempted to gain clues as to the conformational status of the NMDA receptor LBDs during stationary gating by investigating how LBD mutations affect whole-cell currents (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

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Semiclosed Conformations of the Ligand-Binding Domains of NMDA Receptors during Stationary Gating

Dai

Zhou

2016

Biophysical Journal

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NMDA receptors are tetrameric ligand-gated ion channels. In the continuous presence of saturating agonists, NMDA receptors undergo stationary gating, in which the channel stochastically switches between an open state that permits ion conductance and a closed state that prevents permeation. The ligand-binding domains (LBDs) of the four subunits are expected to have closed clefts in the channel-open state. On the other hand, there is little knowledge about the conformational status of the LBDs in the channel-closed state during stationary gating. To probe the latter conformational status, Kussius and Popescu engineered interlobe disulfide cross-links in NMDA receptors and found that the cross-linking produced stationary gating kinetics that differed only subtly from that produced by agonist binding. These authors assumed that the cross-linking immobilized the LBDs in cleft-closed conformations, and consequently concluded that throughout stationary gating, agonistbound LBDs also stayed predominantly in cleft-closed conformations and made only infrequent excursions to cleft-open conformations. Here, by calculating the conformational free energies of cross-linked and agonist-bound LBDs, we assess whether cross-linking actually traps the LBDs in cleft-closed conformations and delineate semiclosed conformations of agonist-bound LBDs that may potentially be thermodynamically and kinetically important during stationary gating. Our free-energy results show that the cross-linked LBDs are not locked in the fully closed form; rather, they sample semiclosed conformations almost as readily as the agonist-bound LBDs. Several lines of reasoning suggest that LBDs are semiclosed in the channel-closed state during stationary gating. Our free-energy simulations suggest possible structural details of such semiclosed LBD conformations, including intra-and intermolecular interactions that serve as alternatives to those in the cleft-closed conformations.

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“…The agonist binds in a pocket located in the cleft between the upper and lower lobes, D1 and D2, respectively. Agonist binding induces closure of the cleft formed between D1 and D2, which is the initial conformational change within a sequence that leads to channel opening (Armstrong and Gouaux, 2000) [see also Hansen et al (2007) and Kumar and Mayer (2013)]. The mechanism by which agonist binding induces channel gating through these conformational changes has been intensively studied to understand how glutamate receptors function.…”

Section: Introductionmentioning

confidence: 99%

Structural Determinants of Agonist Efficacy at the Glutamate Binding Site ofN-Methyl-d-Aspartate Receptors

et al. 2013

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N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels assembled from GluN1 and GluN2 subunits. We used a series of N-hydroxypyrazole-5-glycine (NHP5G) partial agonists at the GluN2 glutamate binding site as tools to study activation of GluN1/GluN2A and GluN1/GluN2D NMDA receptor subtypes. Using two-electrode voltage-clamp electrophysiology, fast-application patch-clamp, and single-channel recordings, we show that propyl-and ethyl-substituted NHP5G agonists have a broad range of agonist efficacies relative to the full agonist glutamate (,1-72%). Crystal structures of the agonist binding domains (ABDs) of GluN2A and GluN2D do not reveal any differences in the overall domain conformation induced by binding of the full agonist glutamate or the partial agonist propyl-NHP5G, which is strikingly different from ABD structures of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoate (AMPA) and kainate receptors bound to full and partial agonists. Subsequent evaluation of relative NHP5G agonist efficacy at GluN2A-GluN2D chimeric subunits implicates the amino-terminal domain (ATD) as a strong determinant of agonist efficacy, suggesting that interdomain interactions between the ABD and the ATD may be a central element in controlling the manner by which agonist binding leads to channel opening. We propose that variation in the overall receptor conformation, which is strongly influenced by the nature of interdomain interactions in resting and active states, mediates differences in agonist efficacy and partial agonism at the GluN2 subunits.

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Functional Insights from Glutamate Receptor Ion Channel Structures

Cited by 126 publications

References 143 publications

Pharmacology and Structural Analysis of Ligand Binding to the Orthosteric Site of Glutamate-Like GluD2 Receptors

Pharmacology and Structural Analysis of Ligand Binding to the Orthosteric Site of Glutamate-Like GluD2 Receptors

Semiclosed Conformations of the Ligand-Binding Domains of NMDA Receptors during Stationary Gating

Structural Determinants of Agonist Efficacy at the Glutamate Binding Site ofN-Methyl-d-Aspartate Receptors

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