Task: Question Generation
Input (English): Nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, stimulates mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulating kinase (ERK), c-jun N-terminal protein kinase (JNK) and p38 MAPK, leading to caspase-independent apoptosis in cultured astrocytes. In view of the previous observation that NO stimulates the activity of the Na(+)/Ca(2+) exchanger (NCX), this study examines the involvement of NCX in cytotoxicity. The specific NCX inhibitor SEA0400 blocked SNP-induced phosphorylation of ERK, JNK and p38 MAPK, and decrease in cell viability. SNP-induced phosphorylation of ERK, JNK and p38 MAPK was blocked by removal of external Ca(2+), and SNP treatment caused an increase in (45)Ca(2+) influx. This increase in (45)Ca(2+) influx was blocked by SEA0400, but not the Ca(2+) channel blocker nifedipine. In addition, SNP-induced (45)Ca(2+) influx and cytotoxicity were reduced in NCX1-deficient cells which were transfected with NCX1 siRNA. Inhibitors of intracellular Ca(2+)-dependent proteins such as calpain and calmodulin blocked SNP-induced ERK phosphorylation and decrease in cell viability. Furthermore, the guanylate cyclase inhibitor LY83583 and the cGMP-dependent protein kinase inhibitor KT5823 blocked SNP-induced cytotoxicity. These findings suggest that NCX-mediated Ca(2+) influx triggers SNP-induced apoptosis in astrocytes, which may be mediated by a cGMP-dependent pathway.
Output (English): The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?