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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 586/3/763    most recent jphysiol.2007.143941v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Erreger, K. Articles by Traynelis, S. F. PubMed PubMed Citation Articles by Erreger, K. Articles by Traynelis, S. F. Related Collections Neuroscience

¹ Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, GA 30322, USA

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.

(Received 27 August 2007; accepted after revision 23 November 2007; first published online 29 November 2007)
Corresponding author S. F. Traynelis: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, GA 30322, USA.  Email: strayne{at}emory.edu

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