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Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12563-8. doi: 10.1073/pnas.0805624105. Epub 2008 Aug 18.

Supralinear potentiation of NR1/NR3A excitatory glycine receptors by Zn2+ and NR1 antagonist.

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  • 1Department of Neurochemistry, Max Planck Institute for Brain Research, Deutschordenstrasse 46, 60528 Frankfurt am Main, Germany.


Coassembly of the glycine-binding NMDA receptor subunits NR1 and NR3A results in excitatory glycine receptors of low efficacy. Here, we report that micromolar concentrations of the divalent cation Zn(2+) produce a 10-fold potentiation of NR1/NR3A receptor responses, which resembles that seen upon antagonizing glycine binding to the NR1 subunit. Coapplication of both Zn(2+) and NR1 antagonist caused a supralinear potentiation, resulting in a >120-fold increase of glycine-activated currents. At concentrations >50 microM, Zn(2+) alone generated receptor currents with similar efficacy as glycine, implying that NR1/NR3A receptors can be activated by different agonists. Point mutations in the NR1 and NR3A glycine-binding sites revealed that both the potentiating and agonistic effects of Zn(2+) are mediated by the ligand-binding domain of the NR1 subunit. In conclusion, Zn(2+) acts as a potent positive modulator and agonist at the NR1 subunit of NR1/NR3A receptors. Our results suggest that this unconventional member of the NMDA receptor family may in vivo be gated by the combined action of glycine and Zn(2+) or a yet unknown second ligand.

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