Zn2+ permeates Ca2+permeable AMPA/kainate channels and triggers selective neural injury

Abstract

BRIEF exposures of cortical cultures to kainate (100μM) plus Zn²⁺ (300μM) cause fluorescence of the Zn²⁺sensitive dye, TS-Q, to appear in virtually all neurons, probably reflecting depolarization and secondary Zn²⁺permeation through voltage-sensitive Ca²⁺ 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 Co²⁺ uptake (Co²⁺(+) neurons), a histochemical technique that identifies neurons expressing Ca²⁺ permeable AMPA/kainate receptor-gated channels. Kainate/Zn²⁺ exposures in Na⁺ containing media with lower (50–100 μM) Zn²⁺ concentrations resulted 24 h later in selective loss of the Co²⁺(+) neurons, suggesting that these channels may permit particularly high rates of Zn²⁺ passage. Thus, direct permeation of synaptically released Zn ⁺ through Ca²⁺permeable AMPA/kainate channels could contribute to selective degeneration of neurons in disease as well as subserving physiological signaling functions.