CA2-PERMEABLE AMPA()KAINATE AND NMDA CHANNELS - HIGH-RATE OF CA2+ INFLUX UNDERLIES POTENT INDUCTION OF INJURY/

Neurodegeneration may occur secondary to glutamate-triggered Ca2+ infl ux through any of three routes: NMDA channels, voltage-sensitive Ca2channels (VSCC), and Ca2+-permeable AMPA/kainate channels (Ca-A/K). Th is study aims to examine Ca2+ ion dynamics in the generation of excito toxic injury by correlating the relative amounts of Ca-45(2+) that flo w into cortical neurons through each of these routes over a 10 min epo ch (''10 min Ca2+ loads;'' a measure of influx rate), with resultant l evels of intracellular free Ca2+ ([Ca2+](i)) and subsequent injury. Ne urons possessing Ca-A/K make up a small subset (similar to 13%) of cor tical neurons in culture, which can be identified by a histochemical s tain based on kainate-stimulated Co2+ uptake (Co2+(+) neurons) and whi ch are unusually vulnerable to AMPA/kainate receptor-mediated injury. Initial studies using brief kainate exposures (to selectively destroy Co2+(+) neurons) along with kainate-triggered Ca-45(2+) influx measure ments suggested that kainate causes rapid Ca2+ influx into Co2+(+) neu rons (comparable to that caused by NMDA), Influx through both Ca-A/K a nd NMDA channels increased proportionately with extracellular Ca2+, su ggesting that these channels have high Ca2+ permeability. When culture s were subjected to exposures that gave similar 10 min Ca2+ loads thro ugh different routes, comparable levels of injury were observed, sugge sting that net intracellular Ca2+ accumulation is a critical determina nt of injury. However, the relationship between [Ca2+](i) and influx w as less direct: although exposures that gave the lowest or highest 10 min Ca2+ loads showed correspondingly lower or higher mean [Ca2+](i) r esponses, there appears to be a wide range of exposures over which ind ividual neuronal differences and sequestration/buffering mechanisms ob scure [Ca2+](i) as a reflection of influx rate.