The N-methyl-D-aspartate (NMDA) receptor (NR) is a ligand-gated channel that carries the slow component of the glutamate-activated postsynaptic current. Divalent metal ions can affect the NR channel activity in a voltage-dependent [Mg(II)-like] or voltage-independent [Zn(II)-like] manner. We have studied the effect of two toxic metals, lead [Pb(II)] and nickel [Ni(II)] on recombinant NR1a-NR2A and NR1a-NR2B channels expressed in RNA-injected Xenopus laevis oocytes or in transiently transfected mammalian HEK293 cells. Pb(II) caused a dose-dependent, but voltage-independent reversible inhibition of NMDA-activated channel activity similar for NR2A and NR2B-containing receptors; it did not modify the single channel conductance, indicating that its binding site is located out of the ionic pathway of permeation. On the contrary, Ni(II) had multiple and complex effects on NR channels. It determined a voltage-dependent, Mg(II)-like block by which the single channel amplitude and the mean open time were reduced in both NR2A and NR2B-containing channels. While high (>100 microM) concentrations caused a dose-dependent reduction of the activity in both channel types, 30 microM determined a voltage-independent decrease in the frequency of NR1a-NR2A channel openings, but an increase in the frequency of NR1a-NR2B channel openings, confirming previous observations of a subunit-dependent effect of this metal. These results were interpreted under the hypothesis that Pb(II) mediates a Zn(II)-like voltage-independent allosteric modulation that, different from Zn(II), is subunit-independent. In contrast, Ni(II) has different modes of action, which are dependent on the NR2 subunit type present in the receptor and are likely to be related to different interaction sites. The NR2B-dependent facilitation bears close similarities with the polyamine-mediated potentiation.