Manganese inhibits NMDA receptor channel function: Implications to psychiatric and cognitive effects

Humans exposed to excess levels of manganese (Mn2+) express psychiatric problems and deficits in attention and learning and memory. However, there is a paucity of knowledge on molecular mechanisms by which Mn2+ produces such effects. We now report that Mn2+ is a potent inhibitor of [3H]-MK-801 binding to the NMDA receptor channel in rat neuronal membrane preparations. The inhibition of [3H]-MK-801 to the NMDA receptor channel by Mn2+ was activity-dependent since Mn2+ was a more potent inhibitor in the presence of the NMDA receptor co-agonists glutamate and glycine (Ki = 35.9 ± 3.1 μM) than in their absence (Ki = 157.1 ± 6.5 μM). We also show that Mn2+ is a NMDA receptor channel blocker since its inhibition of [3H]-MK-801 binding to the NMDA receptor channel is competitive in nature. That is, Mn2+ significantly increased the affinity constant (Kd) with no significant effect on the maximal number of [3H]-MK-801 binding sites (Bmax). Under stimulating conditions, Mn2+ was equipotent in inhibiting [3H]-MK-801 binding to NMDA receptors expressed in neuronal membrane preparations from different brain regions. However, under basal, non-stimulated conditions, Mn2+ was more potent in inhibiting NMDA receptors in the cerebellum than other brain regions. We have previously shown that chronic Mn2+ exposure in non-human primates increases Cu2+, but not zinc or iron concentrations in the basal ganglia [Guilarte TR, Chen M-K, McGlothan JL, Verina T, Wong DF, Zhou Y, Alexander M, Rohde CA, Syversen T, Decamp E, Koser AJ, Fritz S, Gonczi H, Anderson DW, Schneider JS. Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates. Exp Neurol 2006a;202:381–90]. Therefore, we also tested the inhibitory effects of Cu2+ on [3H]-MK-801 binding to the NMDA receptor channel. The data shows that Cu2+ in the presence of glutamate and glycine is a more potent inhibitor of the NMDA receptor than Mn2+. Our findings suggest that the inhibitory effect of Mn2+ and/or Cu2+ on the NMDA receptor may produce a deficit in glutamatergic transmission in the brain of individuals exposed to excess levels of Mn2+ and produce neurological dysfunction.