Ns. Chen et al., DIFFERENTIAL SENSITIVITY OF RECOMBINANT N-METHYL-D-ASPARTATE RECEPTORSUBTYPES TO ZINC INHIBITION, Molecular pharmacology, 51(6), 1997, pp. 1015-1023
Zinc has been shown to be present in synaptic vesicles of a subset of
glutamatergic boutons and is believed to be core-leased with glutamate
at these synapses, A variety of studies have suggested that zinc migh
t play a role in modulation of excitatory transmission, as well as exc
itotoxicity, by inhibiting N-methyl-D-aspartate (NMDA)-type glutamate
receptors. To further investigate the modulatory effects of zinc on NM
DA receptors of different subunit compositions, we coexpressed the rec
ombinant subunit NR1 with NR2A and/or NR2B in HEK 293 cells. In whole-
cell patch-clamp recordings from these transfected cells, zinc inhibit
ed 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, similar to 40% of the
peak current was inhibited by zinc in a voltage-independent manner wi
th an IC50 value of 5.0 +/- 1.6 nhl and at a V-H value of -60 mV; the
remainder was blocked at a second, voltage-dependent site with an IC50
value of 79 +/- 18 mu M. In contrast, NR1/NR2B currents showed nearly
complete inhibition at a voltage-independent site with an IC50 value
of 9.5 +/- 3.3 mu M. Cells cotransfected with NR1, NR2A, and NR2B show
ed zinc sensitivity intermediate between that characteristic of NR1/NR
2A and that of NR1/NR2B. Furthermore, zinc accelerated the macroscopic
desensitization of both NR1/NR2A and NR1/NR2B in a dose-dependent man
ner, apparently independently of glycine-sensitive desensitization and
Ca2+-dependent inactivation; maximal effects were to decrease desensi
tization time constants for NR1/NR2A by similar to 75% and for NR1/NR2
B by similar to 90%. Differential modulation of NR1/NR2A and NR1/NR2B
currents by zinc may play a role in regulating NMDA receptor-induced s
ynaptic plasticity and neurotoxicity.