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Zinc Deficiency Decreases the Concentration of N-Methyl-D-Aspartate Receptors in Guinea Pig Cortical Synaptic Membranes^1,2,

Department of Biochemistry, University of Missouri, Columbia, MO 65211

Zinc deficiency in guinea pigs decreases glutamate-stimulated calcium uptake in cortical synaptosomes. Glutamate not only stimulates calcium uptake but also potentiates the binding of the drug dizocilpine (MK-801) to an internal site of the N-methyl-D-aspartate receptor/calcium channel, a subtype of the glutamate receptor. The purpose of this study was to determine whether the effect of zinc deficiency on calcium uptake by glutamate-stimulated synaptosomes is related to N-methyl-D-aspartate receptor number or function, as measured by MK-801 binding. Immature guinea pigs consumed a low zinc (<1 mg/kg) diet ad libitum or an adequate zinc (100 mg/kg) diet, either ad libitum or restricted to maintain weight similar to that of the low zinc animals. Binding of MK-801 to cortical membranes was measured first in the presence of saturating concentrations of glutamate or N-methyl-D-aspartate in combination with glycine. Zinc deficiency significantly reduced the concentration of MK-801 binding sites (20%) regardless of the potentiating agonist used, but had no effect on binding affinity. The binding of MK-801 in response to 1, 10 and 100 µmol/L glycine, in the presence of 100 nmol/L glutamate, was then measured and found to be significantly reduced (12%). The results suggest that zinc deficiency decreases the number of functional N-methyl-D-aspartate receptor/channels in cortical membranes, probably because of impaired channel opening.

KEY WORDS: • N-methyl-D-aspartate receptors • zinc status • cortical membranes • guinea pigs • MK-801

¹ Supported in part by NRICG/U.S. Department of Agriculture grant no. 91-37200-6286.

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

³ To whom correspondence should be addressed.

Manuscript received 21 November 1994. Revision accepted 24 February 1995.