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

Proceedings of the National Academy of Sciences of the United States of America
Christian MadryBodo Laube

Abstract

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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Citations

Sep 4, 2009·The Journal of Pharmacology and Experimental Therapeutics·C Thetford Smothers, John J Woodward
Sep 23, 2010·The Journal of Pharmacology and Experimental Therapeutics·Blaise Mathias CostaDaniel T Monaghan
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Nov 15, 2018·Nature Communications·Teddy GrandPierre Paoletti

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