Extracellular ATP mediates necrotic cell swelling in SN4741 dopaminergic neurons through P2X7 receptors
Extracellular ATP mediates necrotic cell swelling in SN4741 dopaminergic neurons through P2X7 receptors
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DOI：
10.1074/jbc.m707915200
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发表时间：
2007-12-28
影响因子：
4.8
通讯作者：
Kim, Kyong-Tai
中科院分区：
文献类型：
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作者：
Jun, Dong-Jae;Kim, Jaeyoon;Kim, Kyong-Tai
细胞外ATP最近被确定为病理损伤后细胞死亡的重要调节因子。SN4741细胞是源自转基因小鼠胚胎黑质的多巴胺能神经元，当其暴露于ATP时，细胞会发生死亡。这种细胞死亡与显著的细胞肿胀、内质网完整性丧失、许多大细胞质空泡的形成以及随后的细胞溶解和DNA释放有关。此外，caspase-3的裂解是细胞凋亡的标志，可由ATP处理诱导。然而，caspase抑制剂不能克服atp诱导的细胞死亡，这表明坏死和凋亡都与atp诱导的细胞死亡有关，表明坏死事件可能超越凋亡过程。在这项研究中，我们还发现P2X(7)受体（P2X(7)Rs）在SN4741细胞中大量表达，并且通过P2X(7)Rs拮抗剂KN62预处理或用小干扰rna敲除P2X(7)Rs，可以逆转atp诱导的肿胀和细胞死亡。因此，受损组织的细胞外ATP释放可能是通过P2X(7)Rs加速坏死SN4741多巴胺能细胞死亡的因素。
Extracellular ATP has recently been identified as an important regulator of cell death in response to pathological insults. When SN4741 cells, which are dopaminergic neurons derived from the substantia nigra of transgenic mouse embryos, are exposed to ATP, cell death occurs. This cell death is associated with prominent cell swelling, loss of ER integrity, the formation of many large cytoplasmic vacuoles, and subsequent cytolysis and DNA release. In addition, the cleavage of caspase-3, a hallmark of apoptosis, is induced by ATP treatment. However, caspase inhibitors do not overcome ATP-induced cell death, indicating that both necrosis and apoptosis are associated with ATP-induced cell death and suggesting that a necrotic event might override the apoptotic process. In this study we also found that P2X(7) receptors (P2X(7)Rs) are abundantly expressed in SN4741 cells, and both ATP-induced swelling and cell death are reversed by pretreatment with the P2X(7)Rs antagonist, KN62, or by knock-down of P2X(7)Rs with small interfering RNAs. Therefore, extracellular ATP release from injured tissues may act as an accelerating factor in necrotic SN4741 dopaminergic cell death via P2X(7)Rs.