Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit.
Zinc inhibits NMDA receptor function through both voltage-dependent and voltage-independent mechanisms. In this report we have investigated the role that the NR1 subunit plays in voltage-independent Zn2+ inhibition. Our data show that inclusion of exon 5 into the NR1 subunit increases the IC50 for voltage-independent Zn2+ inhibition from 3-fold to 10-fold when full length exon 22 is also spliced into the mature NR1 transcript and the NMDA receptor complex contains the NR2A or NR2B subunits; exon 5 has little effect on Zn2+ inhibition of receptors that contain NR2C and NR2D. Mutagenesis within exon 5 indicates that the same residues that control proton inhibition, including Lys211, also control the effects of exon 5 on Zn2+ inhibition. Amino acid exchanges within the NR1 subunit but outside exon 5 (E181Q, E339Q, E342Q, N616R, N616Q, D669N, D669E, C744A, and C798A) that are known to decrease the pH sensitivity also decrease the Zn2+ sensitivity, and concentrations of spermine that relieve tonic proton inhibition also relieve Zn2+ inhibition. In summary, our results define the subunit composition of Zn2+-sensitive NMDA receptors and provide evidence for structural convergence of three allosteric regulators of receptor function: protons, polyamines, and Zn2+.
Department of Pharmacology, Emory University, Rollins Research Center, Altanta, Georgia 30322, USA.
S F
SF
Traynelis
M F
MF
Burgess
F
F
Zheng
P
P
Lyuboslavsky
J L
JL
Powers
D000818:Animals; D004274:DNA, Recombinant; D004594:Electrophysiology; D005091:Exons / Q000187:drug effects; D005260:Female; D009154:Mutation / Q000502:physiology; D009865:Oocytes; D011073:Polyamines / Q000494:pharmacology; D011522:Protons; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics; D013096:Spermine / Q000378:metabolism / Q000494:pharmacology; D014982:Xenopus laevis; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*
D004274:DNA, Recombinant; D011073:Polyamines; D011522:Protons; D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; D015032:Zinc