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Kinsmen Laboratory of Neurological Research, Departments of
Psychiatry and Physiology, University of British Columbia,
Vancouver, British Columbia V6T 1Z3 Canada
Zinc has been shown to be present in synaptic vesicles of a subset of
glutamatergic boutons and is believed to be coreleased with glutamate
at these synapses. A variety of studies have suggested that zinc might
play a role in modulation of excitatory transmission, as well as
excitotoxicity, by inhibiting
N-methyl-D-aspartate (NMDA)-type glutamate
receptors. To further investigate the modulatory effects of zinc on
NMDA receptors of different subunit compositions, we coexpressed the
recombinant subunit NR1 with NR2A and/or NR2B in HEK 293 cells. In
whole-cell patch-clamp recordings from these transfected cells, zinc
inhibited peak glutamate-evoked current responses in a noncompetitive
manner, but there were significant differences between the receptor
subtypes in sensitivity to zinc inhibition. For NR1/NR2A, ~40% of
the peak current was inhibited by zinc in a voltage-independent manner
with an IC50 value of 5.0 ± 1.6 nM and at
a VH value of 
60 mV; the
remainder was blocked at a second, voltage-dependent site with an
IC50 value of 79 ± 18 µM. In
contrast, NR1/NR2B currents showed nearly complete inhibition at a
voltage-independent site with an IC50 value of 9.5 ± 3.3 µM. Cells cotransfected with NR1, NR2A, and NR2B
showed zinc sensitivity intermediate between that characteristic of
NR1/NR2A and that of NR1/NR2B. Furthermore, zinc accelerated the
macroscopic desensitization of both NR1/NR2A and NR1/NR2B in a
dose-dependent manner, apparently independently of glycine-sensitive
desensitization and Ca2+-dependent inactivation; maximal
effects were to decrease desensitization time constants for NR1/NR2A by
~75% and for NR1/NR2B by ~90%. Differential modulation of
NR1/NR2A and NR1/NR2B currents by zinc may play a role in regulating
NMDA receptor-induced synaptic plasticity and neurotoxicity.
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