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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >The Na+/Ca2+ exchanger-mediated Ca2+ influx triggers nitric oxide-induced cytotoxicity in cultured astrocytes.
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The Na+/Ca2+ exchanger-mediated Ca2+ influx triggers nitric oxide-induced cytotoxicity in cultured astrocytes.

机译：Na + / Ca2 +交换子介导的Ca2 +内流在培养的星形胶质细胞中触发一氧化氮诱导的细胞毒性。

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摘要

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.
机译：一氧化氮（NO）参与许多病理状况，包括神经退行性疾病。我们以前发现，NO供体硝普钠（SNP）可以刺激丝裂原激活的蛋白激酶（MAPK），例如细胞外信号调节激酶（ERK），c-jun N端蛋白激酶（JNK）和p38 MAPK，导致培养的星形胶质细胞不依赖胱天蛋白酶的凋亡。鉴于以前的观察结果，NO刺激Na（+）/ Ca（2+）交换子（NCX）的活性，这项研究检查了NCX在细胞毒性中的参与。特定的NCX抑制剂SEA0400阻止SNP诱导的ERK，JNK和p38 MAPK磷酸化，并降低细胞活力。 SNP诱导的ERK，JNK和p38 MAPK的磷酸化被外部Ca（2+）的去除所阻止，并且SNP处理导致（45）Ca（2+）内流的增加。 （45）Ca（2+）流入量的这种增加被SEA0400阻止，但Ca（2+）通道阻滞剂硝苯地平没有被阻止。此外，SNP诱导的（45）Ca（2+）流入和细胞毒性在NCX1缺陷细胞中被NCX1 siRNA转染减少。细胞内Ca（2+）依赖蛋白如钙蛋白酶和钙调蛋白的抑制剂阻止了SNP诱导的ERK磷酸化并降低了细胞活力。此外，鸟苷酸环化酶抑制剂LY83583和依赖cGMP的蛋白激酶抑制剂KT5823阻断了SNP诱导的细胞毒性。这些发现表明，NCX介导的Ca（2+）内流触发星形胶质细胞中SNP诱导的凋亡，这可能是由cGMP依赖性途径介导的。

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