title: NCX and NCKX operation in ischemic neurons.
abstract: 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 [Ca2+] ([Ca2+]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 [Ca2+]c to about 30 microM. These high [Ca2+]c elevations depend on external Ca2+ and can be prevented by removing Na+ or by simultaneously inhibiting NMDA and AMPA/kainate receptors. These data indicate that [Ca2+]c elevations during AD result from Na+ influx via either NMDA or AMPA/kainate channels. The mechanism of the Na-dependent [Ca2+]c elevations may involve a reversal of plasmalemmal Na+/Ca2+ (NCX) and/or Na+/Ca2+ + K+ (NCKX) exchangers. KB-R7943, an NCX inhibitor, suppresses a fraction of the Na-dependent Ca2+ influx during AD. Therefore, Ca2+ influx via NCX and a KB-R7943-resistant pathway (possibly NCKX) is involved. Inhibition of the Na-dependent Ca2+ 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 Ca2+ 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.
authors: Department of Psychiatry, The Psychiatric Institute, 1601 W. Taylor St., Room 334W, Chicago, IL 60612, USA. Lkiedr@psych.uic.edu
authors: Lech
authors: L
authors: Kiedrowski
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology; D002545:Brain Ischemia / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D009474:Neurons / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000502:physiology*; D020521:Stroke / Q000503:physiopathology
chemical_list: D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium