Pb2+ modulates the NMDA-receptor-channel complex.

The actions of Pb2+ on NMDA channel currents of acutely dissociated hippocampal CA1- and CA3-neurones from adult rats activated by aspartate plus glycine (asp/gly) were examined. A fast reversible and a slow irreversible response to Pb2+ were found. Pb2+ applied simultaneously with asp/gly decreased an inward current. The threshold concentration was below 2 microM, the current was reduced > 90% at concentrations over 100 microM. The decrease of the asp/gly activated current showed no voltage dependence. Opening of NMDA channels was not necessary for Pb(2+)-action, as preincubation in 50 microM Pb(2+)-containing external solution for several seconds dramatically reduced the response to asp/gly/Pb2+. This effect was reversed within 2 to 5 s of wash. Presence of Pb2+ or asp/Pb2+ or glycine/Pb2+ in the external solution did not prevent recovery of the NMDA receptor/channel complex from desensitization. Prolonged perfusion of a cell with the asp/gly/Pb(2+)-containing external solution resulted in an irreversible decrease of the asp/gly current, whereas the amplitude of the asp/gly/Pb2+ response did not change over the duration of an experiment. We conclude that Pb2+ modulates NMDA channel activity via interaction with the NMDA/glycine receptor: as a result the channel current decreases.