The Glial Sodium-Calcium Exchanger: A New Target for Nitric Oxide- Mediated Cellular Toxicity

The plasma membrane Na+/Ca2+ exchanger (NCX) is a bidirectional ion transporter that couples the translocation of Na+ in one direction with that of Ca2+ in the opposite direction. This system contributes to the regulation of intracellular Ca2+ concentration via the forward mode (Ca2+ efflux) or the reverse mode (Ca2+ influx). We have previously demonstrated that the Ca2+ paradox, an in vitro reperfusion model, causes the sustained activation of the reverse mode of the NCX, the disruption of Ca2+ homeostasis, and subsequent delayed apoptotic-like death in astrocytes. In addition, we found that the nitric oxide (NO)-cyclic GMP signaling pathway inhibits Ca2+ paradox-mediated astrocyte apoptosis, while a high concentration of NO induces cytotoxicity. In this way, Ca2+ and NO may work together in the pathogenesis of several cells in the central nervous system. Concerning the role of NCX in NO cytotoxicity, we have found, using the specific inhibitor of NCX 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), that NCX is involved in NOinduced cytotoxicity in cultured microglia, astrocytes, and neuronal cells. This review summarizes the pathological roles of the NCX as a new target for NO-mediated cellular toxicity, based on our studies on NO-NCX-mediated glial toxicity.