title: Calcium influx through receptor-operated channel induces mitochondria-triggered paraptotic cell death.
abstract: We address the specific role of cytoplasmic Ca(2+) overload as a cell death trigger by expressing a receptor-operated specific Ca(2+) channel, vanilloid receptor subtype 1 (VR1), in Jurkat cells. Ca(2+) uptake through the VR1 channel, but not capacitative Ca(2+) influx stimulated by the muscarinic type 1 receptor, induced sustained intracellular [Ca(2+)] rises, exposure of phosphatidylserine, and cell death. Ca(2+) influx was necessary and sufficient to induce mitochondrial damage, as assessed by opening of the permeability transition pore and collapse of the mitochondrial membrane potential. Ca(2+)-induced cell death was inhibited by ruthenium red, protonophore carbonyl cyanide m-chlorophenylhydrazone, or cyclosporin A treatment, as well as by Bcl-2 expression, indicating that this process requires mitochondrial calcium uptake and permeability transition pore opening. Cell death occurred without caspase activation, oligonucleosomal/50-kilobase pair DNA cleavage, or release of cytochrome c or apoptosis inducer factor from mitochondria, but it required oxidative/nitrative stress. Thus, Ca(2+) influx triggers a distinct program of mitochondrial dysfunction leading to paraptotic cell death, which does not fulfill the criteria for either apoptosis or necrosis.
authors.affiliation: Instituto de Biologia y Genética Molecular, CSIC-Universidad de Valladolid, Facultad de Medicina, Ramón y Cajal 7, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Jambrina
authors.forename: Roberto
authors.initials: R
authors.lastname: Alonso
authors.forename: Marta
authors.initials: M
authors.lastname: Alcalde
authors.forename: Maria
authors.initials: M
authors.lastname: del Carmen Rodríguez
authors.forename: Antonio
authors.initials: A
authors.lastname: Serrano
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-A
authors.forename: Javier
authors.initials: J
authors.lastname: García-Sancho
authors.forename: Manuel
authors.initials: M
authors.lastname: Izquierdo
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004396:Coloring Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins; D006801:Humans; D020287:In Situ Nick-End Labeling; D007476:Ionophores / Q000494:pharmacology; D019169:Jurkat Cells; D007700:Kinetics; D008164:Luminescent Proteins / Q000378:metabolism; D008564:Membrane Potentials; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D009584:Nitrogen / Q000378:metabolism; D018384:Oxidative Stress; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D012430:Ruthenium Red / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism; D014162:Transfection
chemical_list: D015220:Calcium Channels; D004396:Coloring Agents; D003574:Cytochrome c Group; D007476:Ionophores; D008164:Luminescent Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D012430:Ruthenium Red; D049452:Green Fluorescent Proteins; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D016572:Cyclosporine; D004247:DNA; D020169:Caspases; D009584:Nitrogen; D002118:Calcium