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Volume 17, Number 15,
Issue of August 1, 1997
pp. 5711-5725
Copyright ©1997 Society for Neuroscience
High-Affinity Zinc Inhibition of NMDA NR1-NR2A Receptors
Received March 31, 1997; revised May 8, 1997; accepted May 13, 1997.
Pierre Paoletti,
Philippe Ascher, and
Jacques Neyton
Laboratoire de Neurobiologie, Centre National de la Recherche
Scientifique Unité de Recherche Associée 1857, Ecole
Normale Supérieure, 75005 Paris, France
Micromolar concentrations of extracellular Zn2+
are known to antagonize native NMDA receptors via a dual mechanism
involving both a voltage-independent and a voltage-dependent
inhibition. We have tried to evaluate the relative importance of these
two effects and their subunit specificity on recombinant NMDA receptors expressed in HEK 293 cells and Xenopus oocytes. The
comparison of NR1a-NR2A and NR1a-NR2B receptors shows that the
voltage-dependent inhibition is similar in both types of receptors but
that the voltage-independent inhibition occurs at much lower
Zn2+ concentrations in NR1a-NR2A receptors
(IC50 in the nanomolar range) than in NR1a-NR2B receptors
(IC50 in the micromolar range). The high affinity of the
effect observed with NR1a-NR2A receptors was found to be attributable
mostly to the slow dissociation of Zn2+ from its
binding site. By analyzing the effects of Zn2+ on
varied combinations of NR1 (NR1a or NR1b) and NR2 (NR2A, NR2B, NR2C),
we show that both the NR1 and the NR2 subunits contribute to the
voltage-independent Zn2+ inhibition. We have
observed further that under control conditions, i.e., in zero nominal
Zn2+ solutions, the addition of low concentrations
of heavy metal chelators markedly potentiates the responses of
NR1a-NR2A receptors, but not of NR1a-NR2B receptors. This result
suggests that traces of a heavy metal (probably
Zn2+) contaminate standard solutions and tonically
inhibit NR1a-NR2A receptors. Chelation of a contaminant metal also
could account for the rapid NR2A subunit-specific potentiations
produced by reducing compounds like DTT or glutathione.
Key words:
NMDA;
zinc;
DTT;
heavy metals;
recombinant receptors;
ionic channels
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