Principal role of NR3 subunits in NR1/NR3 excitatory glycine receptor function.
Calcium-permeable N-methyl-d-aspartate (NMDA) receptors are tetrameric cation channels composed of glycine-binding NR1 and glutamate-binding NR2 subunits, which require binding of both glutamate and glycine for efficient channel gating. In contrast, receptors assembled from NR1 and NR3 subunits function as calcium-impermeable excitatory glycine receptors that respond to agonist application only with low efficacy. Here, we show that antagonists of and substitutions within the glycine-binding site of NR1 potentiate NR1/NR3 receptor function up to 25-fold, but inhibition or mutation of the NR3 glycine binding site reduces or abolishes receptor activation. Thus, glycine bound to the NR1 subunit causes auto-inhibition of NR1/NR3 receptors whereas glycine binding to the NR3 subunits is required for opening of the ion channel. Our results establish differential roles of the high-affinity NR3 and low-affinity NR1 glycine-binding sites in excitatory glycine receptor function.
Madry
Christian
C
Abteilung Neurochemie, Max-Planck-Institut für Hirnforschung, Deutschordenstr. 46, 60528 Frankfurt, Germany.
Mesic
Ivana
I
Bartholomäus
Ingo
I
Nicke
Annette
A
Betz
Heinrich
H
Laube
Bodo
B
D000818:Animals; D005998:Glycine / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism*; D021122:Protein Subunits; D018009:Receptors, Glycine / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
C409466:NR1 NMDA receptor; C464437:NR3A NMDA receptor; D021122:Protein Subunits; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine