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Calcium influx through receptor-operated channel induces mitochondria-triggered paraptotic cell death

AuthorsJambrina, Enrique; Alonso, Roberto ; Alcalde, Marta; Rodríguez, María del Carmen ; Serrano, Antonio; Martínez-A, Carlos; García-Sancho, Javier ; Izquierdo, Manuel
Issue Date2003
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 278(16): 14134-14145 (2003)
AbstractWe address the specific role of cytoplasmic Ca2+ overload as a cell death trigger by expressing a receptor-operated specific Ca2+ channel, vanilloid receptor sub-type 1 (VR1), in Jurkat cells. Ca2+ uptake through the VR1 channel, but not capacitative Ca2+ influx stimulated by the muscarinic type 1 receptor, induced sustained intracellular [Ca2+] rises, exposure of phosphatidylserine, and cell death. Ca2+ 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. Ca2+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, Ca2+ influx triggers a distinct program of mitochondrial dysfunction leading to paraptotic cell death, which does not fulfill the criteria for either apoptosis or necrosis.
DescriptionFunctional expression of GFP-VR1 Ca2+ channel. Single-cell [Ca2+]c image kinetic analysis of short pulse-treated cells expressing GFP-VR1. Transiently transfected JHM12 cells were loaded with fura 4F and subjected to digital imaging fluorescence microscopy, and [Ca2+]c images were obtained as indicated under “Experimental Procedures.” The first color frame (GFP) corresponds to the green fluorescence image, and subsequent ratiometric images for [Ca2+]c were recorded every 5 s. Representative frames corresponding to the different [Ca2+]c peaks were taken at the indicated time points . [Ca2+]c profiles were averaged for the two cell populations (GFP-VR1+, n = 45; GFP-VR1−, n = 62) and represented at the bottom of the Fig. 2 In Jambrina et al.. Cells were superfused during the indicated periods with the different solutions containing the VR1 agonist capsaicin (0.1 μm, CAPS) and the HM1R agonist carbachol (50 μm, CBCh), in the presence or the absence (Ca2+0) of calcium in the external medium. The capsaicin-sensitive cells corresponded to cells expressing GFP-VR1, as assessed by superimposition of fluorescence images excited at 490 nm (to visualize GFP) and the ratiometric Ca2+ images (fura-4F, excited at 340 and 380 nm; see upper panels in Fig. 2 A of Jambrina et al.). Color code included in Fig. 2; Blue represents 0 calcium whereas red is high calcium.
Publisher version (URL)https://doi.org/10.1074/jbc.M211388200
Identifiersdoi: 10.1074/jbc.M211388200
issn: 0021-9258
e-issn: 1083-351X
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