Ca(2+)-permeable AMPA/kainate and NMDA channels: high rate of Ca2+ influx underlies potent induction of injury.
Neurodegeneration may occur secondary to glutamate-triggered Ca2+ influx through any of three routes: NMDA channels, voltage-sensitive Ca2+ channels (VSCC), and Ca(2+)-permeable AMPA/kainate channels (Ca-A/K). This study aims to examine Ca2+ ion dynamics in the generation of excitotoxic injury by correlating the relative amounts of 45Ca2+ that flow into cortical neurons through each of these routes over a 10 min epoch ("10 min Ca2+ loads;" a measure of influx rate), with resultant levels of intracellular free Ca2+ ([Ca2+]) and subsequent injury. Neurons possessing Ca-A/K make up a small subset (approximately 13%) of cortical neurons in culture, which can be identified by a histochemical stain based on kainate-stimulated Co2+ uptake (Co2+ (+) neurons) and which are unusually vulnerable to AMPA/kainate receptor-mediated injury. Initial studies using brief kainate exposures (to selectively destroy Co2+ (+) neurons) along with kainate-triggered 45Ca2+ influx measurements suggested that kainate causes rapid Ca2+ influx into Co2+ (+) neurons (comparable to that caused by NMDA). Influx through both Ca-A/K and NMDA channels increased proportionately with extracellular Ca2+, suggesting that these channels have high Ca2+ permeability. When cultures were subjected to exposures that gave similar 10 min Ca2+ loads through different routes, comparable levels of injury were observed, suggesting that net intracellular Ca2+ accumulation is a critical determinant of injury. However, the relationship between [Ca2+]i and influx was less direct: although exposures that gave the lowest or highest 10 min Ca2+ loads showed correspondingly lower or higher mean [Ca2+]i responses, there appears to be a wide range of exposures over which individual neuronal differences and sequestration/buffering mechanisms obscure [Ca2+]i as a reflection of influx rate.
Lu
Y M
YM
Department of Neurology, University of California, Irvine 92717-4290, USA.
Yin
H Z
HZ
Chiang
J
J
Weiss
J H
JH
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D007608:Kainic Acid / Q000378:metabolism*; D051379:Mice / Q000196:embryology; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000378:metabolism*; D009410:Nerve Degeneration; D009994:Osmolar Concentration; D010539:Permeability; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism*
D015220:Calcium Channels; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid; D002118:Calcium