Ion regulation of phosphatidylserine and phosphatidylethanolamine outside-inside translocation in human erythrocytes

Bitbol, Michel; Fellmann, Pierre; Zachowski, Alain; Devaux, Philippe F.

doi:10.1016/0005-2736(87)90376-2

Cited by 186 publications

(118 citation statements)

References 32 publications

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“…Flippase is known to be sensitive towards the cellular influx of Ca 2+ in such a way that its translocating activity is significantly affected at [Ca 2+ ] i of 0.2 µM or higher (Bitbol et al, 1987;Daleke, 2003). HNE and acrolein have also been found to disrupt Ca 2+ homeostasis, again interfering with PtdSer asymmetry (Castegna et al, 2004;Mohmmad Abdul and Butterfield, 2005).…”

Section: Discussionmentioning

confidence: 99%

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Lange

Cenini

Piroddi

et al. 2008

Neurobiology of Disease

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Oxidative stress, a hallmark of Alzheimer disease (AD), has been shown to induce lipid peroxidation and apoptosis disrupting cellular homeostasis. Normally, the aminophospholipid phosphatidylserine (PtdSer) is asymmetrically distributed on the cytosolic leaflet of the lipid bilayer. Under oxidative stress conditions, asymmetry is altered, characterized by the appearance of PtdSer on the outer leaflet, to initiate the first stages of an apoptotic process. PtdSer asymmetry is actively maintained by the ATP-dependent translocase flippase, whose function is inhibited if covalently bound by lipid peroxidation products, 4-hydroxynonenal (HNE) and acrolein, within the membrane bilayer in which they are produced. Additionally, pro-apoptotic proteins Bax and caspase-3 have been implemented in the oxidative modification of PtdSer resulting in subsequent asymmetric collapse, while antiapoptotic protein Bcl-2 has been found to prevent this process.The current investigation focused on detection of PtdSer on the outer leaflet of the bilayer in synaptosomes from brain of subjects with AD and amnestic mild cognitive impairment (MCI), as well as expression levels of apoptosis-related proteins Bcl-2, Bax, and caspase-3. Fluorescence and Western blot analysis suggest PtdSer exposure on the outer leaflet is significantly increased in brain from subjects with MCI and AD contributing to early apoptotic elevation of pro-and anti-apoptotic proteins and finally neuronal loss. MCI is considered a possible transition point between normal cognitive aging and probable AD. Brain from subjects with MCI is reported to have increased levels of tissue oxidation; therefore, the results of this study could mark the progression of patients with MCI into AD. This study contributes to a model of apoptosis-specific oxidation of phospholipids consistent with the notion that PtdSer exposure is required for apoptotic-cell death.

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Section: Discussionmentioning

confidence: 99%

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Lange

Cenini

Piroddi

et al. 2008

Neurobiology of Disease

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“…When cytosolic levels of Ca 2+ are elevated in erythrocytes or platelets, PS appears on the cell surface within minutes. 43,44 Although Ca 2+ inactivates the translocase, 45 this event alone is insufficient to bring PS rapidly to the cell surface because of the slow rate of passive diffusion of phospholipids across the bilayer. 46 However, Ca 2+ also activates a non-specific, bi-directional lipid flipsite, distinct from the translocase and termed the scramblase.…”

Section: Mechanisms For Maintenance and Loss Of Ps Asymmetrymentioning

confidence: 99%

Phosphatidylserine, a death knell

2001

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Virtually every cell in the body restricts phosphatidylserine (PS) to the inner leaflet of the plasma membrane by energydependent transport from the outer to the inner leaflet of the bilayer. Apoptotic cells of all types rapidly randomize the asymmetric distribution, bringing PS to the surface where it serves as a signal for phagocytosis. A myriad of phagocyte receptors have been implicated in the recognition of apoptotic cells, among them a PS receptor, yet few ligands other than PS have been identified on the apoptotic cell surface. Since apoptosis and the associated exposure of PS on the cell surface is probably over 600 million years old, it is not surprising that evolution has appropriated aspects of this process for specialized purposes such as blood coagulation, membrane fusion and erythrocyte differentiation. Failure to efficiently remove apoptotic cells may contribute to inflammatory responses and autoimmune diseases resulting from chronic, inappropriate exposure of PS. Cell Death and Differentiation (2001) 8, 551 ± 563.

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“…Fax: (46) 8-329-041. E-mail: mark.hampton@imm.ki.se 4bbreviations: PS, phosphatidylserine; TNF, tumour necrosis factor; EGTA, ethylene glycol-bis(~-aminoethylether)-N,N,N',N'-tetraacetic ~cid; BAPTA-AM, acetoxymethyl ester of 1,2-bis(2-aminophenoxy)-:~'thane-N,N'-tetraacetic acid; FITC, fluorescein isothiocyanate; ICE, nterleukin-l[3 converting enzyme; PARP, poly(ADP-ribose) polymertse; AMC, amino-4-methylcoumarin; cmk, chloromethylketone; CHX, cycloheximide; FSC, forward scatter; PMSF, phenylmethylsulronyl fluoride vates the aminophospholipid translocase which normally constrains PS to the inner leaflet [13], but this alone is insufficient for exposure. Another protein is proposed to mediate the scrambling of membrane phospholipids [14], although there is debate as to whether there is a general phospholipid scrambling or a specific translocation of PS [15].…”

Section: ~ Introductionmentioning

confidence: 99%

“…Platelet activation causes rapid increase in intracellular 2a 2+, and pharmacological modulation with Ca 2+ ionophores ~r Ca2+-ATPase inhibitors can stimulate the exposure of large lmounts of PS by platelets within minutes [12]. Ca 2+ inacti- vates the aminophospholipid translocase which normally constrains PS to the inner leaflet [13], but this alone is insufficient for exposure. Another protein is proposed to mediate the scrambling of membrane phospholipids [14], although there is debate as to whether there is a general phospholipid scrambling or a specific translocation of PS [15].…”

mentioning

confidence: 99%

Involvement of extracellular calcium in phosphatidylserine exposure during apoptosis

et al. 1996

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The appearance of phosphatidylserine (PS) on the outer surface of apoptotic cells is an important signal for their ingestion. In platelets, elevation of intracellular Ca 2÷ with thapsigargin can trigger large amounts of PS exposure within minutes. We detected PS exposure in U937 promonocytes and J urkat T-cells after incubation with thapsigargin, but in only 10% of the cells, and it took up to 6 h to occur. Tumor necrosis factor and anti-Fas antibody rapidly trigger apoptosis in these cells, and chelation of extracellular Ca 2+ with 5 mM EGTA inhibited PS exposure by 65% and 50%, respectively. Chelation of intracellular Ca 2+ with BAPTA-AM had no effect. Other parameters of apoptosis, including cell blebbing, shrinkage, nuclear fragmentation, activation of the ICE-like proteases, and fodrin cleavage, were not inhibited by extracelhilar EGTA. We conclude that while an elevation of intracellular Ca 2+ is an ineffective trigger of apoptosis in the cells investigated, extracellular Ca 2+ is required for efficient PS exposure during apoptosis.Key words: Apoptosis; Phosphatidylserine; Ca2+; l'hapsigargin; Tumor necrosis factor; Anti-fas ~. IntroductionCells undergoing apoptosis are ingested by both neighbour~ng cells and professional phagocytes. This prevents any initammation and tissue damage that could occur upon lysis of ~he dying cell. One important mechanism for the recognition , ~f apoptotic cells is the expression of phosphatidylserine (PS) ~n their outer surface [I]. PS is normally constrained to the nner leaflet of the plasma membrane [2], but disruption of ,his asymmetry has been reported in a variety of cell types mdergoing apoptosis [3][4][5][6][7][8][9].It has been known for many years that PS is exposed on the ,,urface of activated platelets, where it plays an important role n the clotting cascade [10]. PS can also be exposed by red ~lood cells and is involved in their clearance from circulation 11]. Platelet activation causes rapid increase in intracellular 2a 2+, and pharmacological modulation with Ca 2+ ionophores ~r Ca2+-ATPase inhibitors can stimulate the exposure of large lmounts of PS by platelets within minutes [12]. Ca 2+ inacti- vates the aminophospholipid translocase which normally constrains PS to the inner leaflet [13], but this alone is insufficient for exposure. Another protein is proposed to mediate the scrambling of membrane phospholipids [14], although there is debate as to whether there is a general phospholipid scrambling or a specific translocation of PS [15]. Reconstituted membranes have been used to study these mechanisms [16], and recently a 37 kDa protein has been extracted from red cell ghosts that can transport labelled phospholipids upon triggering with CaA variety of studies implicate Ca 2+ in the regulation of apoptosis [18]. Disruption of Ca 2+ homeostasis can trigger apoptosis [19], an increase in the concentration of intracellular Ca 2~ has been reported in some apoptotic models [20], and Ca 2+ chelators have been observed to block apoptosis [21]. In other models...

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Ion regulation of phosphatidylserine and phosphatidylethanolamine outside-inside translocation in human erythrocytes

Cited by 186 publications

References 32 publications

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Phosphatidylserine, a death knell

Involvement of extracellular calcium in phosphatidylserine exposure during apoptosis

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