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The Journal of Neuroscience, August 15, 1998, 18(16):6163-6175
Control of Voltage-Independent Zinc Inhibition of NMDA Receptors by the NR1 Subunit
Stephen F. Traynelis1, Michele F. Burgess2, Fang Zheng1, Polina Lyuboslavsky1, and Jennifer L. Powers3 1 Department of Pharmacology, Emory University, Rollins Research Center, Altanta, Georgia 30322, 2 Georgia Department of Natural Resources, Environmental Protection Division, Atlanta, Georgia 30334, and 3 Department of Chemistry, Kennesaw State University, Kennesaw, Georgia 30144
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+.
Key words: NMDA receptors; zinc; protons; RNA splicing; polyamines; site-directed mutagenesis
Copyright © 1998 Society for Neuroscience 0270-6474/98/18166163-13$05.00/0
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