Calcium Influx through Receptor-operated Channel Induces Mitochondria-triggered Paraptotic Cell Death

Jambrina, Enrique; Alonso, Roberto; Alcalde, Marta Carreras; Rodrı́guez, Marı́a del Carmen; Serrano, Antonio; Martı́nez-A, Carlos; García‐Sancho, Javier; Izquierdo, Manuel

doi:10.1074/jbc.m211388200

Cited by 110 publications

(80 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The disruption of mitochondrial Ca 2+ homeostasis has been suggested to be a major cause of cell damage during conditions of oxidative stress (Richter and Frei, 1988;Kim et al, 1998). In addition, it has been reported that 6-OHDA induces Ca 2+ release from mitochondria (Reynolds, 1999;Bae et al, 2003;Jambrina et al, 2003). In the present study, ROS increase by 6-OHDA was not Redox stress and [Ca 2+ ]i increase can lead to mitochondrial Ca 2+ overload and the mitochondrial permeability transition (MPT) (Armstrong, 2006).…”

Section: Discussionmentioning

confidence: 43%

“…More recently, it was shown that an increase in cytosolic Ca 2+ concentrations leads to a mitochondrial calcium overload (Lee et al, 2002), and that the inhibition of mitochondrial calcium uptake has been found to be antiapoptotic in several cell death models (Reynolds, 1999;Bae et al, 2003;Jambrina et al, 2003). However, the relationship between ROS and [Ca 2+ ]i in the 6-OHDA-induced cell death signaling pathway has not been clarified.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death

Park

Lee²,

Park³

et al. 2007

Exp Mol Med

View full text Add to dashboard Cite

Abstract6-Hydroxydopamine (6-OHDA) is a neurotoxin and is commonly used to generate experimental models of Parkinson's disease (PD). In this study, we investigated the signaling molecules involved in the 6-OHDA-induced cell death using a neuronal catecholaminergic cell line (SK-N-SH cells), and the protective effect of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-OHDA-induced neuronal death. 6-OHDA significantly increased levels of reactive oxygen species (ROS), intracellular Ca 2+ ([Ca 2+ ] i ), and p38 phosphorylation. In addition, this ROS increase by 6-OHDA was reduced by pretreatment with N-acetylcysteine (NAC), a free radical scavenger, but not by bis-(o-aminophenoxy)-ethane-N,N,N,Ntetraacetic acid (BAPTA), a Ca 2+ chelator. However, the [Ca 2+ ] i increase induced by 6-OHDA was suppressed by NAC. Moreover, pretreatment with NAC or BAPTA significantly prevented the 6-OHDAinduced increases in p38 phosphorylation, Bax/ Bcl-2 ratio, and caspase-3 activity. Although 6-OHDA-increased phosphorylation of p38 was prevented by NAC or BAPTA, inhibition of p38 by SB203580 did not suppress ROS, Bax/Bcl-2 ratio, or caspase-3 activity increases, and only partially prevented 6-OHDA-induced cell death, thus demonstrating that p38 activation is a component of a signaling pathway leading to the initiation of 6-OHDA-induced cell death, which acts in parallel with an ROS-Ca 2+ -Bcl-2-caspase-3 pathway. Moreover, fustin not only suppressed 6-OHDA-induced cell death in a concentration-dependent manner but also blocked 6-OHDA-induced increases in ROS, [Ca 2+ ] i , Bax/Bcl-2 ratio, caspase-3 activity, and p38 phosphorylation. These results suggest that fustin exerts neuroprotection against 6-OHDA-induced cell death.

show abstract

Section: Discussionmentioning

confidence: 43%

Section: Introductionmentioning

confidence: 99%

Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death

Park

Lee²,

Park³

et al. 2007

Exp Mol Med

View full text Add to dashboard Cite

show abstract

“…Previously, two other groups of researchers have reported that Ca þ 2 ion disregulation induces paraptosis. 45,46 In preliminary studies, an elevated intracellular Ca þ 2 level was maintained, as seen in fura-2 fluorescence studies, when BK channel activators are added (Hoa, unpublished data). BK channels are known as Ca þ 2 -dependent-voltage-dependent K þ channels, so the present work is consistent with that of Rao et al 45 and Jambrina et al 46 Thus, it is possible that there are common effector mechanisms involving disrupted ionic homeostasis that can lead to paraptosis.…”

Section: Cell Cytotoxicity Occurred After 8-12 H Of Continuous Bk Chamentioning

confidence: 92%

Human monocytes kill M-CSF-expressing glioma cells by BK channel activation

Hoa

Zhang

Delgado

et al. 2007

Laboratory Investigation

View full text Add to dashboard Cite

In this study, human monocytes/macrophages were observed to kill human U251 glioma cells expressing membrane macrophage colony-stimulating factor (mM-CSF) via a swelling and vacuolization process called paraptosis. Human monocytes responded to the mM-CSF-transduced U251 glioma cells, but not to viral vector control U251 glioma cells (U251-VV), by producing a respiratory burst within 20 min. Using patch clamp techniques, functional big potassium (BK) channels were observed on the membrane of the U251 glioma cell. It has been previously reported that oxygen indirectly regulates BK channel function. In this study, it was demonstrated that prolonged BK channel activation in response to the respiratory burst induced by monocytes initiates paraptosis in selected glioma cells. Forced BK channel opening within the glioma cells by BK channel activators (phloretin or pimaric acid) induced U251 glioma cell swelling and vacuolization occurred within 30 min. U251 glioma cell cytotoxicity, induced by using BK channel activators, required between 8 and 12 h. Swelling and vacuolization induced by phloretin and pimaric acid was prevented by iberiotoxin, a specific BK channel inhibitor. Confocal fluorescence microscopy demonstrated BK channels co-localized with the endoplasmic reticulum and mitochondria, the two targeted organelles affected in paraptosis. Iberiotoxin prevented monocytes from producing death in mM-CSF-expressing U251glioma cells in a 24 h assay. This study demonstrates a novel mechanism whereby monocytes can induce paraptosis via the disruption of internal potassium ion homeostasis.

show abstract

“…Living cells expressing GFP-CD63 were attached to fibronectin-coated glass-bottom 35 mm culture dishes (Mat-Tek, Ashland, MA, USA) at 24-48 h post-transfection, and stimulated in medium without phenol red (37 ºC). 70 ISs between transfected Jurkat cells and SEE-pulsed (1 μg/ml), CMAC-labeled Raji cells were analyzed as described. 9 In mouse cell IS experiments, CMAC-labeled EL-4 cells were SEB-pulsed (1 μg/ml) and challenged with T lymphoblasts from WT mice at a 1 : 1 ratio.…”

Section: Methodsmentioning

confidence: 99%

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

et al. 2015

View full text Add to dashboard Cite

Multivesicular bodies (MVBs) are endocytic compartments that enclose intraluminal vesicles (ILVs) formed by inward budding from the limiting membrane of endosomes. In T lymphocytes, these ILV contain Fas ligand (FasL) and are secreted as 'lethal exosomes' following activation-induced fusion of the MVB with the plasma membrane. Diacylglycerol (DAG) and diacylglycerol kinase α (DGKα) regulate MVB maturation and polarized traffic, as well as subsequent secretion of pro-apoptotic exosomes, but the molecular basis underlying these phenomena remains unclear. Here we identify protein kinase D (PKD) family members as DAG effectors involved in MVB genesis and secretion. We show that the inducible secretion of exosomes is enhanced when a constitutively active PKD1 mutant is expressed in T lymphocytes, whereas exosome secretion is impaired in PKD2-deficient mouse T lymphoblasts and in PKD1/3-null B cells. Analysis of PKD2-deficient T lymphoblasts showed the presence of large, immature MVB-like vesicles and demonstrated defects in cytotoxic activity and in activation-induced cell death. Using pharmacological and genetic tools, we show that DGKα regulates PKD1/2 subcellular localization and activation. Our studies demonstrate that PKD1/2 is a key regulator of MVB maturation and exosome secretion, and constitutes a mediator of the DGKα effect on MVB secretory traffic. Exosomes are nanovesicles that form as intraluminal vesicles (ILVs) inside multivesicular bodies (MVBs) and are then secreted by numerous cell types. 1 ILVs are generated by inward budding of late endosome limiting membrane in a precisely regulated maturation process. 2,3 Two main pathways are involved in MVB maturation. 4,5 In addition to the ESCRT (endosomal complex required for traffic) proteins, 6 there is increasing evidence that lipids such as lyso-bisphosphatidic acid (LBPA), 7 ceramides 8 and diacylglycerol (DAG) 9 contribute to this membrane invagination process.Exosomes participate in many biological processes related to T-cell receptor (TCR)-triggered immune responses, including T lymphocyte-mediated cytotoxicity and activationinduced cell death (AICD), antigen presentation and intercellular miRNA exchange. [10][11][12][13][14][15] The discovery of exosome involvement in these responses increased interest in the regulation of exosome biogenesis and secretory traffic, with special attention to the contribution of lipids such as ceramide and DAG, as well as DAG-binding proteins. 14,16-21 These studies suggest that positive and negative DAG regulators may control secretory traffic. By transforming DAG into phosphatidic acid (PA), diacylglycerol kinase α (DGKα) is essential for the negative control of DAG function in T lymphocytes. 22 DGKα translocates transiently to the T-cell membrane after human muscarinic type 1 receptor (HM1R) triggering or to the immune synapse (IS) after TCR stimulation; at these subcellular locations, DGKα acts as a negative modulator of phospholipase C (PLC)-generated DAG. 23,24 The secretory vesicle pathway involves several DAGc...

show abstract

Calcium Influx through Receptor-operated Channel Induces Mitochondria-triggered Paraptotic Cell Death

Cited by 110 publications

References 48 publications

Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death

Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death

Human monocytes kill M-CSF-expressing glioma cells by BK channel activation

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

Contact Info

Product

Resources

About