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

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 Zn2+ 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 Zn2+ and NR1 antagonist caused a supralinear potentiation, resulting in a > 120-fold increase of glycine-activated currents. At concentrations >50 mu M, Zn2+ 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 Zn2+ are mediated by the ligand-binding domain of the NR1 subunit. In conclusion, Zn2+ 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 Zn2+ or a yet unknown second ligand.