Kl. Xu et al., Necrotic cell death in C-elegans requires the function of calreticulin andregulators of Ca2+ release from the endoplasmic reticulum, NEURON, 31(6), 2001, pp. 957-971
In C. elegans, a hyperactivated MEC-4(d) ion channel induces necrotic-like
neuronal death that is distinct from apoptosis. We report that null mutatio
ns in calreticulin suppress both mec-4(d)-induced cell death and the necrot
ic cell death induced by expression of a constitutively activated Gas subun
it. RNAi-mediated knockdown of calnexin, mutations in the ER Ca2+ release c
hannels unc-68 (ryanodine receptor) or itr-1 (inositol 1,4,5 triphosphate r
eceptor), and pharmacological manipulations that block ER Call release also
suppress death. Conversely, thapsigargin-induced ER Ca2+ release can resto
re mec-4(d)-induced cell death when calreticulin is absent. We conclude tha
t high [Ca2+](i) is a requirement for necrosis in C. elegans and suggest th
at an essential step in the death mechanism is release of ER-based Ca2+ sto
res. ER-driven Ca2+ release has previously been implicated in mammalian nec
rosis, suggesting necrotic death mechanisms may be conserved.