Kinetic basis of partial agonism at NMDA receptors

Kussius, Cassandra L.; Popescu, Gabriela

doi:10.1038/nn.2361

Cited by 68 publications

(141 citation statements)

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“…Conceptual Models of GluN1/GluN2B Receptor Activation. In recent years, a number of conceptual models for NMDA receptor gating have been proposed (Banke and Traynelis, 2003;Popescu and Auerbach, 2003;Auerbach and Zhou, 2005;Erreger et al, 2005;Schorge et al, 2005;Dravid et al, 2008;Kussius and Popescu, 2009). Together with structural information, these conceptual models may allow determination of steps involved in receptor activation that define macroscopic currents and synaptic activity.…”

Section: Resultsmentioning

confidence: 99%

Effect of Ifenprodil on GluN1/GluN2B N-Methyl-D-aspartate Receptor Gating

et al. 2012

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Ifenprodil is an allosteric inhibitor of GluN1/GluN2B N-methyl-Daspartate receptors. Despite its widespread use as a prototype for drug development and a subtype-selective tool for physiologic experiments, its precise effect on GluN1/GluN2B gating is yet to be fully understood. Interestingly, recent crystallographic evidence identified that ifenprodil, unlike zinc, binds at the interface of the GluN1/GluN2B amino terminal domain dimer by an induced-fit mechanism. To delineate the effect of this unique binding on GluN1/GluN2B receptor gating, we recorded steadystate currents from cell-attached and outside-out patches. At pH 7.9 in cell-attached patches, ifenprodil increased the occupancy of the long-lived shut conformations, thereby reducing the open probability of the receptor with no change in the mean open time. In addition, ifenprodil selectively affected the area of shut time constants, but not the time constants themselves. Kinetic analyses suggested that ifenprodil prevents the transition of the receptor to an open state and increases its dwell time in an intrinsically occurring closed conformation or desensitized state. We found distinct differences in the action of ifenprodil at GluN1/GluN2B in comparison with previous studies on the effect of zinc on GluN1/ GluN2A gating, which may arise due to their unique binding sites. Our data also uncover the potential pH-dependent action of ifenprodil on gating. At a low pH (pH 7.4), but not pH 7.9, ifenprodil reduces the mean open time of GluN1/GluN2B receptors, which may be responsible for its usefulness as a context-dependent inhibitor in conditions like ischemia and stroke, when the pH of the extracellular milieu becomes acidic.

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Section: Resultsmentioning

confidence: 99%

Effect of Ifenprodil on GluN1/GluN2B N-Methyl-D-aspartate Receptor Gating

et al. 2012

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“…Future work may reveal why HCY decreases peak amplitude of GluN2B NMDAR responses while continuing to reduce desensitization. It may be that HCY resembles partial GLY site agonists such as L-alanine, which reduce GLYdependent NMDAR desensitization but decrease receptor opening probability relative to full agonists Kussius and Popescu 2009).…”

Section: Discussionmentioning

confidence: 99%

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Bolton

Phillips

Constantine‐Paton

2013

Journal of Neurophysiology

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Bolton AD, Phillips MA, Constantine-Paton M. Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition. J Neurophysiol 110: 1567-1582, 2013. First published July 17, 2013 doi:10.1152/jn.00809.2012.-N-methyl-D-aspartate receptors (NMDARs) have been linked to schizophrenia because agents that bind the receptor, like ketamine and phencyclidine, are capable of inducing schizophrenia-like symptoms. Here we show that the amino acid homocysteine (HCY), which is increased in the blood of schizophrenia patients, reduces desensitization of NMDARs in cultured mouse neurons, human embryonic kidney cells transfected with GluN1 ϩ GluN2A, GluN2B, or GluN2D subunits, and hippocampal slices. HCY also alters the peak amplitude of NMDAR currents, depending on the GluN2 subunit the receptor contains; GluN1 ϩ GluN2A-containing NMDARs show an increase in peak amplitude when exposed to HCY, while GluN1 ϩ GluN2B-containing NMDARs show a decrease in peak amplitude. Both peak amplitude and desensitization effects of HCY can be occluded by saturating the NMDAR with glycine. Since glycine concentrations are not saturating in the brain, HCY could play an NMDAR-modulating role in the nervous system. We also show that HCY shares characteristics with glutamate and suggest that HCY affects both the agonist and coagonist site of the NMDAR.

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“…NMDA receptors have robust single-channel activity, with a single conductance level (1). Kinetic analyses of single-channel currents have revealed that during stationary gating, the channelclosed state contains three components (C 3 , C 2 , and C 1 ) outside desensitization and the channel-open state contains two or more components, which are often collectively denoted as O (9)(10)(11)(12). The molecular nature of these kinetic components remains unknown, although mutational effects on the populations and transition rates of these components have provided some hints (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

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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Kinetic basis of partial agonism at NMDA receptors

Cited by 68 publications

References 43 publications

Effect of Ifenprodil on GluN1/GluN2B N-Methyl-D-aspartate Receptor Gating

Effect of Ifenprodil on GluN1/GluN2B N-Methyl-D-aspartate Receptor Gating

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

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

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