Xu K, Tavernarakis N, Driscoll M
Department of Molecular Biology and Biochemistry, A232, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08855, USA.
Neuron. 2001 Sep 27;31(6):957-71. doi: 10.1016/s0896-6273(01)00432-9.
In C. elegans, a hyperactivated MEC-4(d) ion channel induces necrotic-like neuronal death that is distinct from apoptosis. We report that null mutations in calreticulin suppress both mec-4(d)-induced cell death and the necrotic cell death induced by expression of a constitutively activated Galpha(S) subunit. RNAi-mediated knockdown of calnexin, mutations in the ER Ca(2+) release channels unc-68 (ryanodine receptor) or itr-1 (inositol 1,4,5 triphosphate receptor), and pharmacological manipulations that block ER Ca(2+) release also suppress death. Conversely, thapsigargin-induced ER Ca(2+) release can restore mec-4(d)-induced cell death when calreticulin is absent. We conclude that high Ca(2+) is a requirement for necrosis in C. elegans and suggest that an essential step in the death mechanism is release of ER-based Ca(2+) stores. ER-driven Ca(2+) release has previously been implicated in mammalian necrosis, suggesting necrotic death mechanisms may be conserved.
在秀丽隐杆线虫中，超活化的MEC-4(d)离子通道会引发一种不同于凋亡的坏死样神经元死亡。我们报告称，钙网蛋白的无效突变可抑制mec-4(d)诱导的细胞死亡以及由组成型活化的Gα(S)亚基表达所诱导的坏死细胞死亡。RNA干扰介导的钙联结蛋白敲低、内质网Ca(2+)释放通道unc-68（兰尼碱受体）或itr-1（肌醇1,4,5-三磷酸受体）的突变，以及阻断内质网Ca(2+)释放的药理学操作也可抑制死亡。相反，当缺乏钙网蛋白时，毒胡萝卜素诱导的内质网Ca(2+)释放可恢复mec-4(d)诱导的细胞死亡。我们得出结论，高细胞内Ca(2+)浓度是秀丽隐杆线虫坏死的必要条件，并表明死亡机制中的一个关键步骤是内质网钙库的释放。内质网驱动的Ca(2+)释放此前已被认为与哺乳动物坏死有关，这表明坏死性死亡机制可能是保守的。
