Zinc inhibition of rat NR1/NR2AN‐methyl‐d‐aspartate receptors

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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 IC50value 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.
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