Trapping of glutamate and glycine during open channel block of rat hippocampal neuron NMDA receptors by 9‐aminoacridine.

Benveniste, Morris; Mayer, Mark L.

doi:10.1113/jphysiol.1995.sp020591

Cited by 96 publications

(93 citation statements)

References 38 publications

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“…In our hypothesized scenario, a shift in the channel's preference for the open state goes hand in hand with an increase in LBD cleft closure, thus explaining the observed decrease in cleft accessibility. By the same reasoning, we can also explain an earlier observation that an open-pore blocker, which maintained the channel in the open conformation but occluded permeating ions, prevented agonist dissociation from the LBD clefts (48).…”

Section: Discussionmentioning

confidence: 61%

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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Section: Discussionmentioning

confidence: 61%

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

Dai

Zhou

2016

Biophysical Journal

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“…The binding characteristics are similar to those described for some of the voltage-dependent blockers of NMDA receptor (MacDonald et al, 1987;Huettner and Bean, 1988). The extent of agonist dependency affects the degree to which the blocker is trapped in the channel, so the blockers range from those that are not trapped [e.g., 9-aminoacridine (Benveniste and Mayer, 1995)] to those that are fully trapped [e.g., MK-801 (Huettner and Bean, 1988)]. If we neglect the differences in the voltage dependency, the action of 3␣5␤S at NMDA receptors is similar to that of 9-aminoacridine, because neither of them are trapped (Benveniste and Mayer, 1995).…”

Section: ␣5␤s Is a Use-dependent Nmda Receptor Inhibitormentioning

confidence: 51%

“…The extent of agonist dependency affects the degree to which the blocker is trapped in the channel, so the blockers range from those that are not trapped [e.g., 9-aminoacridine (Benveniste and Mayer, 1995)] to those that are fully trapped [e.g., MK-801 (Huettner and Bean, 1988)]. If we neglect the differences in the voltage dependency, the action of 3␣5␤S at NMDA receptors is similar to that of 9-aminoacridine, because neither of them are trapped (Benveniste and Mayer, 1995). It has been proposed that the lack of complete trapping is an important factor that accounts for the favorable tolerability of certain channel-blocking NMDA receptor antagonists as drugs in the treatment of neurodegenerative diseases (Mealing et al, 2001).…”

Section: ␣5␤s Is a Use-dependent Nmda Receptor Inhibitormentioning

confidence: 99%

20-Oxo-5β-Pregnan-3α-yl Sulfate Is a Use-Dependent NMDA Receptor Inhibitor

Petrović¹,

Sedlacek²,

Hořák³

et al. 2005

J. Neurosci.

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NMDA receptors are ligand-gated ion channels permeable to calcium and play a critical role in excitatory synaptic transmission, synaptic plasticity, and excitotoxicity. They are heteromeric complexes of NR1 combined with NR2A-D and/or NR3A-B subunits that are activated by glutamate and glycine and whose activity is modulated by allosteric modulators. In this study, patch-clamp recordings from human embryonic kidney 293 cells expressing NR1/NR2 receptors were used to study the molecular mechanism of the endogenous neurosteroid 20-oxo-5␤-pregnan-3␣-yl sulfate (3␣5␤S) action at NMDA receptors. 3␣5␤S was a twofold more potent inhibitor of responses mediated by NR1/NR2C-D receptors than those mediated by NR1/NR2A-B receptors. The structure of the extracellular loop between the third and fourth transmembrane domains of the NR2 subunit was found to be critical for the neurosteroid inhibitory effect. The degree of 3␣5␤S-induced inhibition of responses to glutamate was voltage independent, with recovery lasting several seconds. In contrast, application of 3␣5␤S in the absence of agonist had no effect on the subsequent response to glutamate made in the absence of the neurosteroid. A kinetic model was developed to explain the use-dependent action of 3␣5␤S at NMDA receptors. In accordance with the model, 3␣5␤S was a less potent inhibitor of NMDA receptor-mediated EPSCs and responses induced by a short application of 1 mM glutamate than of those induced by a long application of glutamate.These results suggest that 3␣5␤S is a use-dependent but voltage-independent inhibitor of NMDA receptors, with more potent action at tonically than at phasically activated receptors. This may be important in the treatment of excitotoxicity-induced neurodegeneration.

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“…Activation of AMPA and kainate receptors by glutamate is thought to involve an initial binding of this amino acid to the S1 segment in the N terminus, followed by interactions with the S2 segment of the extracellular loop (17). Upon the binding of glutamate, the two lobes of the channel formed by the S1 and S2 segments may move together, perhaps accounting for agonist trapping and desensitization (18). A single-site mutation in the S1 region of GluR3 (L507Y) is sufficient to eliminate desensitization without changing most other properties of binding and channel gating (19).…”

Section: Figmentioning

confidence: 99%

The Lurcher Mutation of an α-Amino-3-hydroxy-5-methyl- 4-isoxazolepropionic Acid Receptor Subunit Enhances Potency of Glutamate and Converts an Antagonist to an Agonist

Taverna

Xiong

Brandes

et al. 2000

Journal of Biological Chemistry

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A point mutation of the GluR␦2 (A654T) glutamate receptor subunit converts it into a functional channel, and a spontaneous mutation at this site is thought to be responsible for the neurodegeneration of neurons in the Lurcher mouse. This mutation is located in a hydrophobic region of the M3 domain of this subunit, and this alanine is conserved throughout many of the glutamate receptors. We show here that site-directed mutagenesis of the homologous alanine (A636T; GluR1-L c ) in the GluR1 AMPA receptor subunit alters its channel properties. The apparent potencies of both kainate and glutamate were increased 85-and 2000-fold, respectively. Furthermore, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)was converted from a competitive antagonist into a potent agonist. Our results demonstrate that a single amino acid within or near the putative second transmembrane region of the GluR1 subunit is critical for the binding/gating properties of this AMPA receptor.Ionotropic postsynaptic glutamate receptors are responsible for most of the rapid excitatory synaptic transmission in the central nervous system. The binding of glutamate to ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) 1 and Nmethyl-D-aspartic acid (NMDA) receptors generates excitatory synaptic currents in which the kinetics are determined by the relatively rapid gating of AMPA and the much slower gating of NMDA channels. Native channels consist of a heteromeric receptor composed of four subunits (1). A family of four different subunits (GluR1, -2, -3, and -4) can contribute to the formation of AMPA receptors, and each subunit can form functional homomeric channels (2, 3).A related subunit, GluR␦2, with 25% homology to AMPA receptors, is found in cerebellar Purkinje cells; a spontaneous mutation of the GluR␦2 subunit is responsible for the neurodegenerative phenotype of the Lurcher mouse (4, 5). The GluR␦2 subunit cannot form functional heteromeric channels (6, 7), but spontaneously gated currents can be recorded in the absence of an agonist for the Lurcher mutation (GluR␦2-L c ) (5). In this mutation, a substitution of a non-polar alanine with polar threonine occurs at position 654. This alanine is also conserved across a wide variety of glutamate receptors including the AMPA receptor subunits. It was postulated that neurons are lost in Lurcher mice as a consequence of spontaneous gating of GluR␦2-L c channels and the resulting chronic depolarization (5).The GluR␦2-L c mutation is of particular interest because it demonstrates that an apparently nonfunctional channel can be converted to a functional one simply by a point mutation in or near the putative second transmembrane region. Mutational analysis of AMPA receptor gating has been targeted primarily to regions of the N terminus as well as the extracellular loop (8), but little attention has been paid to the possible role of the second transmembrane region in the gating of AMPA channels. To explore the possible role of this region in channel gating, we constructed a mutated GluR1 (flop) subunit wit...

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Trapping of glutamate and glycine during open channel block of rat hippocampal neuron NMDA receptors by 9‐aminoacridine.

Cited by 96 publications

References 38 publications

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

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

20-Oxo-5β-Pregnan-3α-yl Sulfate Is a Use-Dependent NMDA Receptor Inhibitor

The Lurcher Mutation of an α-Amino-3-hydroxy-5-methyl- 4-isoxazolepropionic Acid Receptor Subunit Enhances Potency of Glutamate and Converts an Antagonist to an Agonist

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