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Author Notes:

Corresponding author: S. F. Traynelis, Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, GA 30322, USA. Email: strayne@emory.edu

We thank Dr. David Wyllie for critical comments on the manuscript.

Subjects:

Research Funding:

This work was supported by a Howard Hughes Predoctoral Fellowship (K.E.), the NIH (NINDS NS36654, S.F.T.), NARSAD (S.F.T.), and the Michael J. Fox Foundation (S.F.T.).

Zinc inhibition of rat NR1/NR2A N-methyl-D-aspartate receptors

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Journal Title:

Journal of Physiology

Volume:

Volume 586, Number Pt 3

Publisher:

, Pages 763-778

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Zinc ions (Zn2+) are localized in presynaptic vesicles at glutamatergic synapses and released in an activity-dependent manner. Modulation of NMDA-type glutamate receptors by extracellular Zn2+ may play an important role under physiological conditions and during pathologies such as ischaemia or seizure. Zn2+ inhibits NMDA receptors containing the NR2A subunit with an IC50 value in the low nanomolar concentration range. Here we investigate at the single-channel level the mechanism of high affinity Zn2+ inhibition of recombinant NR1/NR2A receptors expressed in HEK293 cells. Zn2+ reversibly decreases the mean single-channel open duration and channel open probability determined in excised outside-out patches, but has no effect on single-channel current amplitude. A parallel series of experiments demonstrates that lowering extracellular pH (increasing proton concentration) has a similar effect on NR1/NR2A single-channel properties as Zn2+. Fitting the sequence of single-channel events with kinetic models suggests that the association of Zn2+ with its binding site enhances proton binding. Modelling further suggests that protonated channels are capable of opening but with a lower open probability than unprotonated channels. These data and analyses are consistent with Zn2+-mediated inhibition of NMDA receptors primarily reflecting enhancement of proton inhibition.

Copyright information:

© 2008 The Authors. Journal compilation © 2008 The Physiological Society

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