Premium
NCX and NCKX Operation in Ischemic Neurons
Author(s) -
KIEDROWSKI LECH
Publication year - 2007
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1387.035
Subject(s) - kainate receptor , chemistry , ampa receptor , depolarization , biophysics , ischemia , extracellular , glutamate receptor , nmda receptor , hippocampal formation , cytosol , penumbra , neuroscience , sodium calcium exchanger , medicine , receptor , biochemistry , intracellular , biology , enzyme
Within the first 2 min of global brain ischemia, extracellular [K + ] ([K + ] o ) increases above 60 mM and [Na + ] o drops to about 50 mM, indicating a massive K + efflux and Na + influx, a phenomenon known as anoxic depolarization (AD). Similar ionic shifts take place during repetitive peri‐infarct depolarizations (PID) in the area penumbra in focal brain ischemia. The size of ischemic infarct is determined by the duration of AD and PID. However, the mechanism of cytosolic [Ca 2+ ] ([Ca 2+ ] c ) elevation during AD or PID is poorly understood. Our data show that the exposure of cultured rat hippocampal CA1 neurons to AD‐like conditions promptly elevates [Ca 2+ ] c to about 30 μM. These high [Ca 2+ ] c elevations depend on external Ca 2+ and can be prevented by removing Na + or by simultaneously inhibiting NMDA and AMPA/kainate receptors. These data indicate that [Ca 2+ ] c elevations during AD result from Na + influx via either NMDA or AMPA/kainate channels. The mechanism of the Na‐dependent [Ca 2+ ] c elevations may involve a reversal of plasmalemmal Na + /Ca 2+ (NCX) and/or Na + /Ca 2+ + K + (NCKX) exchangers. KB‐R7943, an NCX inhibitor, suppresses a fraction of the Na‐dependent Ca 2+ influx during AD. Therefore, Ca 2+ influx via NCX and a KB‐R7943‐resistant pathway (possibly NCKX) is involved. Inhibition of the Na‐dependent Ca 2+ influx is likely to decrease ischemic brain damage. No drugs are known that are able to inhibit the KB‐R7943‐resistant component of Na‐dependent Ca 2+ influx during AD. The present data encourage development of such agents as potential therapeutic means to limit ischemic brain damage after stroke or heart attack.