TY - JOUR T1 - Control of Voltage-Independent Zinc Inhibition of NMDA Receptors by the NR1 Subunit JF - The Journal of Neuroscience JO - J. Neurosci. SP - 6163 LP - 6175 DO - 10.1523/JNEUROSCI.18-16-06163.1998 VL - 18 IS - 16 AU - Stephen F. Traynelis AU - Michele F. Burgess AU - Fang Zheng AU - Polina Lyuboslavsky AU - Jennifer L. Powers Y1 - 1998/08/15 UR - http://www.jneurosci.org/content/18/16/6163.abstract N2 - 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+. ER -