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Multiple sites of action of neomycin, Mg²⁺ and spermine on the NMDA receptors of rat hippocampal CA1 pyramidal neurones

Wei-Yang Lu, Zhi-Gang Xiong, Beverley A. Orser * and John F. MacDonald ¹

1. The effects of neomycin on NMDA-evoked currents in isolated CA1 hippocampal pyramidal neurones were investigated and single channel activity was examined in outside-out patches taken from cultured hippocampal neurones. The effects of neomycin on two combinations of NMDA receptor subunits (NR1a-NR2A and NR1a-NR2B) expressed in human embryonic kidney (HEK293) cells were also studied.

2. Neomycin (0·01-1 mM) caused a potentiation of NMDA-activated currents in all neurones examined. No evidence of a voltage-dependent depression was observed in whole-cell recordings.

3. In outside-out patch recordings relatively low concentrations (30 and 100 µM) of neomycin caused a voltage-dependent reduction in single channel current amplitude as well as a large increase in the frequency of channel opening.

4. In saturating concentrations of glycine, neomycin enhanced NMDA-activated currents and this glycine-independent enhancement was confirmed using recombinant NR1a-NR2B receptors. Neomycin substantially increased the potency of glycine for the receptor by reducing the rate of dissociation of glycine from the receptor. Neomycin demonstrated a glycine-dependent enhancement of currents mediated by the NR1a-NR2A combination of subunits but a paradoxical depression was observed in saturating concentrations of glycine.

5. Neomycin increased the rate of deactivation of glutamate-activated currents consistent with neomycin causing a reduction in the affinity of the receptor for agonist.

6. These results indicate that neomycin has multiple and complex effects on NMDA receptors.

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