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Molecular Determinants of Coordinated Proton and Zinc Inhibition of N-methyl-D-aspartate NR1/NR2A Receptors

Chian-Ming Low, Fang Zheng, Polina Lyuboslavsky and Stephen F. Traynelis
Proceedings of the National Academy of Sciences of the United States of America
Vol. 97, No. 20 (Sep. 26, 2000), pp. 11062-11067
Stable URL: http://www.jstor.org/stable/123252
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Molecular Determinants of Coordinated Proton and Zinc Inhibition of N-methyl-D-aspartate NR1/NR2A Receptors
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Abstract

Modulation of the N-methyl-D-aspartate (NMDA)-selective glutamate receptors by extracellular protons and Zn2+ may play important roles during ischemia in the brain and during seizures. Recombinant NR1/NR2A receptors exhibit a much higher apparent affinity for voltage-independent Zn2+ inhibition than receptors with other subunit combinations. Here, we show that the mechanism of this apparent high-affinity, voltage-independent Zn2+ inhibition for NR2A-containing receptors results from the enhancement of proton inhibition. We also show that the N-terminal leucine/isoleucine/valine binding protein (LIVBP)-like domain of the NR2A subunit contains critical determinants of the apparent high-affinity, voltage-independent Zn2+ inhibition. Mutations H42A, H44G, or H128A greatly increase the Zn2+ IC50 (by up to ≈ 700-fold) with no effect on the potencies of glutamate and glycine or on voltage-dependent block by Mg2+. Furthermore, the amino acid residue substitution H128A, which mediates the largest effect on the apparent high-affinity Zn2+ inhibition among all histidine substitutions we tested, is also critical to the pH-dependency of Zn2+ inhibition. Our data revealed a unique interaction between two important extracellular modulators of NMDA receptors.

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