Sequential Shrinkage and Swelling Underlie P2X7-Stimulated Lymphocyte Phosphatidylserine Exposure and Death

Taylor, Simon; González-Begné, Mireya; Dewhurst, Stephen; Chimini, Giovanna; Higgins, Christopher F.; Melvin, James E.; Elliott, James I.

doi:10.4049/jimmunol.180.1.300

Cited by 70 publications

(66 citation statements)

References 46 publications

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“…Others, however, have also failed to demonstrate an important role for PANX1 (Faria et al, 2005;Schachter et al, 2008;Taylor et al, 2008). Our findings argue in favour of the receptor itself forming an intrinsic pathway for the influx of cationic dyes.…”

Section: An Intrinsic Pathway For Cation Dye Influxsupporting

confidence: 47%

Splice-variants of the P2X7 receptor reveal differential agonist-dependence and functional coupling with pannexin-1

Boumechache

Robinson

et al. 2012

Journal of Cell Science

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SummaryP2X7 receptors function as ATP-gated cation channels but also interact with other proteins as part of a larger signalling complex to mediate a variety of downstream responses that are dependent upon the cell type in which they are expressed. Receptor-mediated membrane permeabilization to large molecules precedes the induction of cell death, but remains poorly understood. The mechanisms that underlie differential sensitivity to NAD are also unknown. By studying alternative variants of the mouse P2X7 receptor we show that sensitivity to NAD is mediated through the P2X7k variant, which has a much more restricted distribution than the P2X7a receptor, but is expressed in T lymphocytes. The altered N-terminus and TM1 of the P2X7k receptor enhances the stability of the active state of this variant compared with P2X7a, thereby increasing the efficacy of NAD-dependent ADP ribosylation as measured by ethidium uptake, a rise in intracellular Ca 2+ and the activation of inward currents. Co-expression of P2X7k and P2X7a receptors reduced NAD sensitivity. P2X7k-receptor-mediated ethidium uptake was also triggered by much lower BzATP concentrations and was insensitive to the P451L single nucleotide polymorphism. P2X7k-receptor-mediated ethidium uptake occurred independently of pannexin-1 suggesting a pathway intrinsic to the receptor. Only for the P2X7aL451 receptor could we resolve a component of dye uptake dependent upon pannexin-1. Signalling occurred downstream of the activation of caspases rather than involving direct cross talk between the channels. However, an in situ proximity assay showed close association between P2X7 receptors and pannexin-1, which would facilitate ATP efflux through pannexin-1 acting in an autocrine manner.

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Section: An Intrinsic Pathway For Cation Dye Influxsupporting

confidence: 47%

Splice-variants of the P2X7 receptor reveal differential agonist-dependence and functional coupling with pannexin-1

Boumechache

Robinson

et al. 2012

Journal of Cell Science

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“…9 Stimulation of this receptor is proin-flammatory, causing release of inflammatory cytokines such as IL-1␤ and IL-18 from macrophages, changes in plasma membrane lipid distribution, and cell death by necrosis or apoptosis. 10,11 A central role for P2X 7 in IL-1␤ secretion via the Nacht Domain-, Leucine-Rich Repeat-, and PYD-Containing Protein 3 (NALP3) inflammasome has been shown in P2X 7 -deficient mice. 12,13 This receptor also has significant prothrombotic effects, 14 causing release of tissue factor-bearing microparticles.…”

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confidence: 99%

P2X7 Deficiency Attenuates Renal Injury in Experimental Glomerulonephritis

Taylor

Turner

Elliott

et al. 2009

Journal of the American Society of Nephrology

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104

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The P2X 7 receptor is a ligand-gated cation channel that is normally expressed by a variety of immune cells, including macrophages and lymphocytes. Because it leads to membrane blebbing, release of IL-1␤, and cell death by apoptosis or necrosis, it is a potential therapeutic target for a variety of inflammatory diseases. Although the P2X 7 receptor is usually not detectable in normal renal tissue, we previously reported increased expression of both mRNA and protein in mesangial cells and macrophages infiltrating the glomeruli in animal models of antibody-mediated glomerulonephritis. In this study, we used P2X 7 -knockout mice in the same experimental model of glomerulonephritis and found that P2X 7 deficiency was significantly renoprotective compared with wild-type controls, evidenced by better renal function, a striking reduction in proteinuria, and decreased histologic glomerular injury. In addition, the selective P2X 7 antagonist A-438079 prevented the development of antibody-mediated glomerulonephritis in rats. These results support a proinflammatory role for P2X 7 in immune-mediated renal injury and suggest that the P2X 7 receptor is a potential therapeutic target.

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“…Only P2X 7 receptors are to date established as having physiological roles in inflammation, mostly via a rapid activation of caspase-1 with subsequent release of the proinflammatory cytokine IL-1␤ from activated macrophages and microglia (15,16). P2X 7 is also an important modulator of T cell functions (17)(18)(19)(20).…”

mentioning

confidence: 99%

P2X1 Ion Channels Promote Neutrophil Chemotaxis through Rho Kinase Activation

Lecut

Frederix

Johnson

et al. 2009

The Journal of Immunology

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ATP, released at the leading edge of migrating neutrophils, amplifies chemotactic signals. The aim of our study was to investigate whether neutrophils express ATP-gated P2X1 ion channels and whether these channels could play a role in chemotaxis. Whole-cell patch clamp experiments showed rapidly desensitizing currents in both human and mouse neutrophils stimulated with P2X1 agonists, αβ-methylene ATP (αβMeATP) and βγMeATP. These currents were strongly impaired or absent in neutrophils from P2X1−/− mice. In Boyden chamber assays, αβMeATP provoked chemokinesis and enhanced formylated peptide- and IL-8-induced chemotaxis of human neutrophils. This agonist similarly increased W-peptide-induced chemotaxis of wild-type mouse neutrophils, whereas it had no effect on P2X1−/− neutrophils. In human as in mouse neutrophils, αβMeATP selectively activated the small RhoGTPase RhoA that caused reversible myosin L chain phosphorylation. Moreover, the αβMeATP-elicited neutrophil movements were prevented by the two Rho kinase inhibitors, Y27632 and H1152. In a gradient of W-peptide, P2X1−/− neutrophils migrated with reduced speed and displayed impaired trailing edge retraction. Finally, neutrophil recruitment in mouse peritoneum upon Escherichia coli injection was enhanced in wild-type mice treated with αβMeATP, whereas it was significantly impaired in the P2X1−/− mice. Thus, activation of P2X1 ion channels by ATP promotes neutrophil chemotaxis, a process involving Rho kinase-dependent actomyosin-mediated contraction at the cell rear. These ion channels may therefore play a significant role in host defense and inflammation.

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Sequential Shrinkage and Swelling Underlie P2X7-Stimulated Lymphocyte Phosphatidylserine Exposure and Death

Cited by 70 publications

References 46 publications

Splice-variants of the P2X7 receptor reveal differential agonist-dependence and functional coupling with pannexin-1

Splice-variants of the P2X7 receptor reveal differential agonist-dependence and functional coupling with pannexin-1

P2X7 Deficiency Attenuates Renal Injury in Experimental Glomerulonephritis

P2X1 Ion Channels Promote Neutrophil Chemotaxis through Rho Kinase Activation

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