Abstract
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+)](i) 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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Animals, Genetically Modified
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Caenorhabditis elegans / cytology*
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Caenorhabditis elegans / growth & development
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Caenorhabditis elegans / metabolism
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Caenorhabditis elegans Proteins*
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Calcium Channels / physiology
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Calcium Signaling / physiology*
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / physiology*
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Calnexin
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Calreticulin
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Cell Size
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Chromosome Mapping
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Endoplasmic Reticulum / metabolism*
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Helminth Proteins / genetics
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Helminth Proteins / physiology*
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Heterotrimeric GTP-Binding Proteins / physiology
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Homeostasis
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Humans
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Inositol 1,4,5-Trisphosphate Receptors
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Ion Transport / drug effects
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Larva
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Membrane Proteins*
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Molecular Sequence Data
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Mutation
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Necrosis
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Nerve Degeneration / genetics
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Nerve Tissue Proteins / physiology*
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Neurons / cytology*
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Neurons / metabolism
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Receptors, Cytoplasmic and Nuclear / physiology
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Recombinant Fusion Proteins / physiology
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Ribonucleoproteins / genetics
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Ribonucleoproteins / physiology*
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Ryanodine Receptor Calcium Release Channel / physiology
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Sequence Alignment
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Sequence Homology, Amino Acid
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Structure-Activity Relationship
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Thapsigargin / pharmacology
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Touch
Substances
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Caenorhabditis elegans Proteins
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Calcium Channels
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Calcium-Binding Proteins
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Calreticulin
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Helminth Proteins
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ITPR1 protein, human
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Inositol 1,4,5-Trisphosphate Receptors
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Mec-4 protein, C elegans
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Membrane Proteins
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Nerve Tissue Proteins
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Receptors, Cytoplasmic and Nuclear
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Recombinant Fusion Proteins
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Ribonucleoproteins
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Ryanodine Receptor Calcium Release Channel
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Unc-68 protein, C elegans
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Calnexin
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Thapsigargin
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Heterotrimeric GTP-Binding Proteins