Gating Reaction Mechanisms for NMDA Receptor Channels

Auerbach, Anthony; Zhou, Yu

doi:10.1523/jneurosci.1471-05.2005

Cited by 57 publications

(97 citation statements)

References 61 publications

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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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“…For one pair of positions, GluN1(Leu-819) and GluN2A(Phe-637), we also observed an interaction with respect to apparent desensitization. NMDA receptors exhibit multiple forms of apparent desensitization or macroscopic current decay in the prolonged presence of agonist (54); the conditions we used in this study were designed to minimize the influence of forms of current decay other than true desensitization, which refers to sojourns of the liganded receptor in one or more long-lived closed states (55)(56)(57) and thus is a form of ion channel gating. In the NMDA receptor, the M3 domain is primarily responsible for gating of the ion channel (46 -48, 51), and we and others have shown that the M4 domain regulates gating of the ion channel (36,52).…”

Section: Discussionmentioning

confidence: 99%

Interactions among Positions in the Third and Fourth Membrane-associated Domains at the Intersubunit Interface of the N-Methyl-d-aspartate Receptor Forming Sites of Alcohol Action

Ren

Zhao

Dwyer

et al. 2012

Journal of Biological Chemistry

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Background:The NMDA receptor is a major target of alcohol action in the brain. Results: Four pairs of residues at the M3-M4 domain intersubunit interfaces interact to regulate gating and alcohol sensitivity. Conclusion: NMDA receptors contain putative sites of alcohol action at the M3-M4 domain interfaces. Significance: Identifying molecular sites of alcohol action on its targets is essential for understanding its actions.

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“…If this structural feature were shared by NMDA receptors, and four pre-M1 helices were to move independently in the agonist-bound receptor, one might imagine these conformational changes could constitute rate limiting and kinetically distinct steps that precede concerted channel opening involving simultaneous rearrangement of all four M3 helices. Single channel studies of agonist-bound NMDA receptors have identified multiple kinetically distinguishable steps that precede channel opening via a concerted pore dilation involving all or no repositioning of M3 transmembrane helices Popescu and Auerbach, 2003;Auerbach and Zhou, 2005;Erreger et al, 2005a;Schorge et al, 2005;Dravid et al, 2008). These rate-limiting and kinetically distinct steps must reflect rate limiting conformational changes that occur before rapid pore dilation (Schorge et al, 2005).…”

Section: Glutamate Receptor Ion Channelsmentioning

confidence: 99%