Brief exposures of cortical cultures to kainate (100 mu M) plus Zn(2+) (300 mu M) cause fluorescence of the Zn(2+) sensitive dye, TS-Q, to appear in virtually all neurons, probably reflecting depolarization and secondary Zn(2+) permeation through voltage-sensitive Ca(2+) channels. However, if Na+ ions are removed from the media (to prevent depolarization), prominent TS-Q fluorescence is still observed in the small subset of neurons labeled by kainate stimulated Co(2+) uptake (Co(2+)(+) neurons), a histochemical technique that identifies neurons expressing Ca(2+) permeable AMPA/kainate receptor-gated channels. Kainate/Zn(2+) exposures in Na+ containing media with lower (50-100 mu M) Zn(2+) concentrations resulted 24 h later in selective loss of the Co(2+)(+) neurons, suggesting that these channels may permit particularly high rates of Zn(2+) passage. Thus, direct permeation of synaptically released Zn(2+) through Ca(2+) permeable AMPA/kainate channels could contribute to selective degeneration of neurons in disease as well as subserving physiological signaling functions.