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 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.
Madry
Christian
C
Department of Neurochemistry, Max Planck Institute for Brain Research, Deutschordenstrasse 46, 60528 Frankfurt am Main, Germany.
Betz
Heinrich
H
Geiger
Jörg R P
JR
Laube
Bodo
B
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D004594:Electrophysiology; D005998:Glycine / Q000378:metabolism* / Q000494:pharmacology; D008845:Microinjections; D009154:Mutation; D009865:Oocytes; D012313:RNA; D018009:Receptors, Glycine / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014982:Xenopus laevis; D015032:Zinc / Q000494:pharmacology*
C409466:NR1 NMDA receptor; C464437:NR3A NMDA receptor; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D012313:RNA; D015032:Zinc; D005998:Glycine