In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 97, No. 20 ( 2000-09-26), p. 11062-11067
Abstract:
Modulation of the N- methyl- d -aspartate (NMDA)-selective
glutamate receptors by extracellular protons and Zn 2+ 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 Zn 2+ inhibition than
receptors with other subunit combinations. Here, we show that the mechanism of this apparent high-affinity, voltage-independent
Zn 2+ 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 Zn 2+ inhibition.
Mutations H42A, H44G, or H128A greatly increase the Zn 2+ IC 50 (by up to ≈700-fold) with no effect on the potencies
of glutamate and glycine or on voltage-dependent block by Mg 2+ . Furthermore, the amino acid residue substitution
H128A, which mediates the largest effect on the apparent high-affinity Zn 2+ inhibition among all histidine substitutions we
tested, is also critical to the pH-dependency of Zn 2+ inhibition. Our data revealed a unique interaction between two
important extracellular modulators of NMDA receptors.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.180307497
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2000
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
Permalink
