DIFFERENTIAL MODULATION BY ZINC AND COPPER OF AMINO-ACID RECEPTORS FROM RAT OLFACTORY-BULB NEURONS

1. The olfactory bulb contains high concentrations of zinc and copper. Whole cell recording techniques were used to examine the modulatory a ctions of zinc and copper on N-methyl-D-aspartate (NMDA), gamma-aminob utyric acid (GABA), and glycine receptors on rat olfactory bulb neuron s in culture and acutely isolated from adult animals. 2. Zinc and copp er were effective antagonists of both NMDA- and GABA-mediated currents . The median inhibiting concentrations (IC(50)s) for zinc were 19 mu M for NMDA receptors and 17 mu M for GABA receptors. The IC(50)s for co pper were 22 mu M for NMDA receptors and 18 mu M for GABA receptors. 3 . Zinc and copper (100 mu M) had no effect on the steady-state, desens itized component of currents evoked by high concentrations of glycine (300 mu M) in contrast, when low, nondesensitizing concentrations of g lycine (30 mu M) were used, 100 mu M zinc dramatically potentiated the current and 100 mu M copper blocked the current. 4. The effects of zi nc and copper on NMDA-, GABA-, or glycine-mediated currents were not v oltage dependent, irrespective of whether the effect was potentiation or inhibition. 5. These results provide the first evidence for an inhi bitory effect of copper on NMDA receptors, and the first evidence that the effects of zinc and copper on glycine receptors are dependent on the state of the receptor. These results suggest that endogenous zinc and copper may act as allosteric neuromodulators of amino acid recepto rs on olfactory bulb neurons. Furthermore, zinc and copper may provide a mechanism for differential modulation of inhibitory transmission be cause of their distinct effects on glycine versus GABA receptors.