Previous studies in newborn piglets have shown that the N-methyl-D-aspartate (NMDA) receptor ion channel complex is modified during hypoxia and is regulated during normoxia by an inhibitory Zn++ binding site within the ion channel. The present study tests the hypothesis that Zn++ modification of the NMDA receptor correlates with a progressive decrease in cerebral cellular energy metabolism induced by hypoxia. Studies were conducted in 11 ventilated piglets - 6 nomoxic and 5 hypoxic. Varying degrees of hypoxia were attained by exposure to decreased oxygen at different concentrations and confimed by brain tissue phosphocreatine (PCr) levels.3[H]MK-801 binding was performed in the presence of 100 μM glutamate, 100 μM glycine, 12.5 nM 3[H]MK-801 and ZnSO4 ranging from [0.05] to [15] mM in P2 membrane fractions. Nonspecific binding was determined in the presence of 10 μM unlabelled MK-801. The Zn++ 50% inhibitory concentration (IC50) and brain tissue PCr levels were determined biochemically. In the normoxic group the mean PCr value was 2.99±1.25 μmol/g brain and IC50 (Zn++) 1.22±0.46 mM (mean±SD). For the group exposed to varying degrees of hypoxia, PCr (μmol/g brain) and IC50(mM) were as follows: (1.14, 1.45), (1.02, 1.25), (0.50, 1.15), (0.42, 1.05) and (0.25, 0.56). The IC50 decreased in a linear relationship as a function of PCr (r = 0.70). The data show that the effect of Zn++ on ion channel opening as measured by 3[H]MK-801 binding is directly correlated with the energy state of the cell and that receptor sensitivity to the inhibitory effect of Zn++ gradually increases as oxidative phosphorylation decreases during hypoxia. We speculate that dephosphorylation of the receptor ion channel site during hypoxia enhances Zn++ binding through an allosteric or conformational change in the receptor allowing increased accessibility of Zn++ to its binding site and that receptor modification may be initiated by subtle decreases in tissue oxygenation in the newborn brain.(Funded by NIH HD 20337, MOD 6-FY94-0135, Wyeth)
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(Spon by: Maria Delivoria-Papadopoulos, M.D.)
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Fritz, K., Zubrow, A., Zhu, A. et al. Zn++ Modification of the NMDA Receptor During Graded Hypoxia in the Cerebral Cortex of Newborn Piglets. † 1724. Pediatr Res 41 (Suppl 4), 290 (1997). https://doi.org/10.1203/00006450-199704001-01743
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DOI: https://doi.org/10.1203/00006450-199704001-01743