Control of voltage-independent Zinc inhibition of NMDA receptors by the NR1 subunit

Stephen F. Traynelis, Michele F. Burgess, Fang Zheng, Polina Lyuboslavsky, Jennifer L. Powers

Research output: Contribution to journalArticlepeer-review

230 Scopus citations

Abstract

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+.

Original languageEnglish
Pages (from-to)6163-6175
Number of pages13
JournalJournal of Neuroscience
Volume18
Issue number16
DOIs
StatePublished - Aug 15 1998

Keywords

  • NMDA receptors
  • Polyamines
  • Protons
  • RNA splicing
  • Site-directed mutagenesis
  • Zinc

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