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 GαS subunit. RNAi-mediated knockdown of calnexin, mutations in the ER Ca2+ release channels unc-68 (ryanodine receptor) or itr-1 (inositol 1,4,5 triphosphate receptor), and pharmacological manipulations that block ER Ca2+ release also suppress death. Conversely, thapsigargin-induced ER Ca2+ release can restore mec-4(d)-induced cell death when calreticulin is absent. We conclude that high [Ca2+]i is a requirement for necrosis in C. elegans and suggest that an essential step in the death mechanism is release of ER-based Ca2+ stores. ER-driven Ca2+ release has previously been implicated in mammalian necrosis, suggesting necrotic death mechanisms may be conserved.
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