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1.
Robson Coutinho-Silva Gladys Corrêa Ali Abdul Sater David M. Ojcius 《Purinergic signalling》2009,5(2):197-204
The purinergic receptor, P2X7, has recently emerged as an important component of the innate immune response against microbial infections. Ligation of P2X7 by ATP can stimulate inflammasome activation and secretion of proinflammatory cytokines, but it can also lead directly to killing of intracellular pathogens in infected macrophages and epithelial cells. Thus, while some intracellular pathogens evade host defense responses by modulating with membrane trafficking or cell signaling in the infected cells, the host cells have also developed mechanisms for inhibiting infection. This review will focus on the effects of P2X7 on control of infection by intracellular pathogens, microbial virulence factors that interfere with P2X7 activity, and recent evidence linking polymorphisms in human P2X7 with susceptibility to infection. 相似文献
2.
The P2X7 receptor in retinal ganglion cells: A neuronal model of pressure-induced damage and protection by a shifting purinergic balance
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Claire H. Mitchell Wennan Lu Huiling Hu Xiulan Zhang David Reigada Mei Zhang 《Purinergic signalling》2009,5(2):241-249
Retinal ganglion cells process the visual signal and transmit it along their axons in the optic nerve to the brain. Molecular, immunohistochemical, and functional analyses indicate that the majority of retinal ganglion cells express the ionotropic P2X7 receptor. Stimulation of the receptor can lead to a rise in intracellular calcium and cell death, although death does not involve the opening of a large diameter pore. Adenosine acting at A3 receptors can attenuate the rise in calcium and death accompanying P2X7 receptor activation, suggesting that dephosphorylation of ATP into adenosine is neuroprotective and that the balance of extracellular purines can influence neuronal survival. Increased intraocular pressure can lead to release of excessive extracellular ATP in the retina and damage ganglion cells by acting on P2X7 receptors, implicating a role for the receptor in the loss of ganglion cell activity in glaucoma. In summary, the activation of P2X7 receptors has both physiologic and pathophysiologic implications for ganglion cell function. These characteristics may also provide an insight into the contributions the P2X7 receptor makes to neurons elsewhere. 相似文献
3.
Shu-Chen Hung Chul Hee Choi Najwane Said-Sadier Larry Johnson Kalina Rosenova Atanasova Hanen Sellami ?zlem Yilmaz David M. Ojcius 《PloS one》2013,8(7)
We have previously reported that Porphyromonas gingivalis infection of gingival epithelial cells (GEC) requires an exogenous danger signal such as ATP to activate an inflammasome and caspase-1, thereby inducing secretion of interleukin (IL)-1β. Stimulation with extracellular ATP also stimulates production of reactive oxygen species (ROS) in GEC. However, the mechanism by which ROS is generated in response to ATP, and the role that different purinergic receptors may play in inflammasome activation, is still unclear. In this study, we revealed that the purinergic receptor P2X4 is assembled with the receptor P2X7 and its associated pore, pannexin-1. ATP induces ROS production through a complex consisting of the P2X4, P2X7, and pannexin-1. P2X7−mediated ROS production can activate the NLRP3 inflammasome and caspase-1. Furthermore, separate depletion or inhibition of P2X4, P2X7, or pannexin-1 complex blocks IL-1β secretion in P. gingivalis-infected GEC following ATP treatment. However, activation via P2X4 alone induces ROS generation but not inflammasome activation. These results suggest that ROS is generated through stimulation of a P2X4/P2X7/pannexin-1 complex, and reveal an unexpected role for P2X4, which acts as a positive regulator of inflammasome activation during microbial infection. 相似文献
4.
Gladys Corrêa Camila Marques da Silva Aline Cristina de Abreu Moreira-Souza Rossiane Claudia Vommaro Robson Coutinho-Silva 《Microbes and infection / Institut Pasteur》2010,12(6):497-504
Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii, which is widespread throughout the world. After active penetration, the parasite is enclosed within a parasitophorous vacuole and survives in the host cell by avoiding, among other mechanisms, lysosomal degradation. A large number of studies have demonstrated the importance of ATP signalling via the P2X7 receptor, as a component of the inflammatory response against intracellular pathogens. Here we evaluate the effects of extracellular ATP on T. gondii infection of macrophages. ATP treatment inhibits the parasite load and the appearance of large vacuoles in the cytoplasm of intracellular parasites. ROS and NO assays showed that only ROS production is involved with the ATP effects. Immunofluorescence showed colocalization of Lamp1 and SAG1 only after ATP treatment, suggesting the formation of phagolysosomes. The involvement of P2X7 receptors in T. gondii clearance was confirmed by the use of P2X7 agonists and antagonists, and by infecting macrophages from P2X7 receptor-deficient mice. We conclude that parasite elimination might occur following P2X7 signalling and that novel therapies against intracellular pathogens could take advantage of activation of purinergic signalling. 相似文献
5.
Sun-Hye Choi Hyeon-Joong Kim Bo-Ra Kim Tae-Joon Shin Sung-Hee Hwang Byung-Hwan Lee Sang-Mok Lee Hyewhon Rhim Seung-Yeol Nah 《Molecules and cells》2013,35(2):142-150
Ginseng, the root of Panax ginseng C.A. Meyer, is used as a general tonic. Recently, we isolated a novel ginsengderived lysophosphatidic acid (LPA) receptor ligand, gintonin. Gintonin activates G protein-coupled LPA receptors with high affinity in cells endogenously expressing LPA receptors, e.g., Xenopus oocytes. P2X receptors are ligandgated ion channels activated by extracellular ATP, and 7 receptor subtypes (P2X1–P2X7) have been identified. Most of the P2X1 receptors are expressed in the smooth muscles of genitourinary organs involved in reproduction. A main characteristic of the P2X1 receptor is rapid desensitization after repeated ATP treatment of cells or tissues expressing P2X1 receptors. In the present study, we examined the effect of gintonin on P2X1 receptor channel activity. P2X1 receptors were heterologously expressed in Xenopus oocytes. ATP treatment of oocytes expressing P2X1 receptors induced large inward currents (I ATP ), but repetitive ATP treatments induced a rapid desensitization of I ATP . Gintonin treatment after P2X1 receptor desensitization potentiated I ATP in a concentration-dependent manner. We further examined the signaling transduction pathways involved in gintonin-mediated potentiation of I ATP . Gintoninmediated I ATP potentiation was blocked by Ki16425, an LPA1/3 receptor antagonist, a PKC inhibitor, a PLC inhibitor, and a PI4-Kinase inhibitor but not by a calcium chelator. In addition, mutations of the phosphoinositide binding site of the P2X1 receptor greatly attenuated the gintonin-mediated I ATP potentiation. These results indicate that G protein-coupled LPA receptor activation by gintonin is coupled to the potentiation of the desensitized P2X1 receptor through a phosphoinositide-dependent pathway. 相似文献
6.
Fabio Bianco Alessio Colombo Laura Saglietti Davide Lecca Maria Pia Abbracchio Michela Matteoli Claudia Verderio 《Purinergic signalling》2009,5(2):233-240
P2X7 receptor is a ligand-gated ion channel, which can induce the opening of large membrane pores. Here, we provide evidence that the receptor induces pore formation in astrocytes cultured from cortex, but not from the hippocampus. Furthermore, P2X7 receptor activation promptly induces p38 mitogen-activated protein kinase (MAPK) phosphorylation in cortical but not in hippocampal astrocytes. Given the role of p38 MAPK activation in pore opening, these data suggest that defective coupling of the receptor to the enzyme could occur in hippocampal cultures. The different capabilities of the receptor to open membrane pores cause relevant functional consequences. Upon pore formation, caspase-1 is activated and pro-IL1-β is cleaved and released extracellularly. The receptor stimulation does not result in interleukin-1beta secretion from hippocampal astrocytes, although the pro-cytokine is present in the cytosol of lipopolysaccharide-primed cultures. These results open the possibility that activation of P2X7 receptors differently influences the neuroinflammatory processes in distinct brain regions. 相似文献
7.
Chul Hee Choi Ralee Spooner Jefferson DeGuzman Theofilos Koutouzis David M. Ojcius Özlem Yilmaz 《Cellular microbiology》2013,15(6):961-976
Ligation of P2X7 receptors with a ‘danger signal’, extracellular ATP (eATP), has recently been shown to result in production of intracellular reactive‐oxygen‐species (ROS) in macrophages. We show that primary gingival epithelial cells (GECs) produce sustained, robust cellular ROS upon stimulation by eATP. The induction of ROS was mediated by P2X7 receptor signalling coupled with NADPH‐oxidase activation, as determined by pharmacological inhibition and RNA interference. Furthermore, Porphyromonas gingivalis, an oral opportunistic pathogen, upregulated the antioxidant glutathione response, modulated eATP‐induced cytosolic and mitochondrial ROS generated through P2X7/NADPH‐oxidase interactome, and subsequently blocked oxidative stress in GECs via temporal secretion of a P. gingivalis effector, nucleoside‐diphosphate‐kinase (Ndk). An ndk‐deficient P. gingivalis mutant lacked the ability to inhibit ROS production and persist intracellularly following eATP stimulation. Treatment with recombinant Ndk significantly diminished eATP‐evoked ROS production. P. gingivalis infection elicited a strong, time‐dependent increase in anti‐oxidativemitochondrial UCP2 levels, whereas ndk‐deficient mutant did not cause any change. The results reveal a novel signalling cascade that is tightly coupled with eATP signalling and ROS regulation. Ndk by P. gingivalis counteracts these antimicrobial signalling activities by secreting Ndk, thus contributing to successful persistence of the pathogen. 相似文献
8.
ATP, acting on P2X7 receptors, stimulates changes in intracellular calcium concentrations, maturation, and release of interleukin-1β (IL-1β), and following prolonged agonist exposure, cell death. The functional effects of P2X7 receptor activation facilitate several proinflammatory processes associated with arthritis. Within the nervous system, these proinflammatory processes may also contribute to the development and maintenance of chronic pain. Emerging data from genetic knockout studies have indicated specific roles for P2X7 receptors in inflammatory and neuropathic pain states. The discovery of multiple distinct chemical series of potent and highly selective P2X7 receptor antagonists have enhanced our understanding of P2X7 receptor pharmacology and the diverse array of P2X7 receptor signaling mechanisms. These antagonists have provided mechanistic insight into the role(s) P2X7 receptors play under pathophysiological conditions. In this review, we integrate the recent discoveries of novel P2X7 receptor-selective antagonists with a brief update on P2X7 receptor pharmacology and its therapeutic potential. 相似文献
9.
Xin Li Xiaoping Qi Lingyin Zhou Wen Fu Fadi W. Abdul-Karim Gregory MacLennan George I. Gorodeski 《Purinergic signalling》2009,5(3):351-368
The P2X7 receptor is an important regulator of epithelial cell growth. The aim of the present study was to better understand the biological
significance of P2X7 receptor expression in normal and cancer human epithelial tissues. P2X7 receptor and messenger RNA (mRNA) levels were determined in human tissues containing epithelial dysplastic, pre- or early
cancerous, and cancer cells, and the levels were compared to those in the corresponding normal epithelial cells within the
same tissue of the same case. P2X7 receptor levels were determined by quantification of immunoreactivity specific to the functional (full-length) P2X7 receptor, and P2X7 mRNA levels were determined by real-time polymerase chain reaction. P2X7 receptor levels in cancer cells were similar (colon adenocarcinoma) or greater (thyroid papillary carcinoma) than those in
the corresponding normal cells. In contrast, in cancer cells of the ectocervix (squamous), endocervix and endometrium (adenocarcinoma),
urinary bladder (transitional cell carcinoma), and breast (ductal and lobular adenocarcinomas), P2X7 receptor levels were lower by about twofold than those in the corresponding normal epithelial cells. Similarly, P2X7 mRNA levels were lower in uterine, bladder, and breast cancer epithelial tissues by about fourfold than those in the corresponding
normal tissues. In addition, P2X7 receptor levels were decreased already in dysplastic ectocervical cells and pre- or early cancerous endometrial and bladder
cells. The data suggest that in epithelia originating from the ectoderm, the uro-genital sinus, and the distal paramesonephric
duct, decreased expression of the P2X7 receptor precedes or coincides with neoplastic changes in those tissues. 相似文献
10.
Lee Hedden Cyril H. Benes Stephen P. Soltoff 《Biochimica et Biophysica Acta (BBA)/General Subjects》2011
Background
The activation of various P2 receptors (P2R) by extracellular nucleotides promotes diverse cellular events, including the stimulation of cell signaling protein and increases in [Ca2+]i. We report that some agents that can block P2X7R receptors also promote diverse P2X7R-independent effects on cell signaling.Methods
We exposed native rat parotid acinar cells, salivary gland cell lines (Par-C10, HSY, HSG), and PC12 cells to suramin, DIDS (4,4′-diisothiocyano stilbene-2,2′-disulfonic acid), Cibacron Blue 3GA, Brilliant Blue G, and the P2X7R-selective antagonist A438079, and examined the activation/phosphorylation of ERK1/2, PKCδ, Src, CDCP1, and other signaling proteins.Results
With the exception of suramin, these agents blocked the phosphorylation of ERK1/2 by BzATP in rat parotid acinar cells; but higher concentrations of suramin blocked ATP-stimulated 45Ca2+ entry. Aside from A438079, these agents increased the phosphorylation of ERK1/2, Src, PKCδ, and other proteins (including Dok-1) within minutes in an agent- and cell type-specific manner in the absence of a P2X7R ligand. The stimulatory effect of these compounds on the tyrosine phosphorylation of CDCP1 and its Src-dependent association with PKCδ was blocked by knockdown of CDCP1, which also blocked Src and PKCδ phosphorylation.Conclusions
Several agents used as P2X7R blockers promote the activation of various signaling proteins and thereby act more like receptor agonists than antagonists.General significance
Some compounds used to block P2 receptors have complicated effects that may confound their use in blocking receptor activation and other biological processes for which they are employed, including their use as blockers of various ion transport proteins. 相似文献11.
Suzana Passos Chaves Eduardo Caio Torres-Santos Camila Marques Vanessa Ribeiro Figliuolo Pedro Muanis Persechini Robson Coutinho-Silva Bartira Rossi-Bergmann 《Microbes and infection / Institut Pasteur》2009,11(10-11):842-849
The purinergic P2X7 receptor is a membrane protein of leucocytes involved in the clearance of intracellular bacteria such as Chlamydia and Mycobacterium. In this work, we investigated the role and modulation of macrophage P2X7R in intracellular infection with the protozoan parasite Leishmania amazonensis. Upon infection, isolated murine macrophages displayed enhanced expression of P2X7R and were significantly more responsive to extracellular ATP (ATPe)-induced pore opening, as demonstrated by the increased uptake of Lucifer Yellow. This was extended to the in vivo situation, where cells from established cutaneous lesions were more sensitive to ATPe than cells from uninfected mice. ATP treatment of infected macrophages inhibited parasite growth, and this was prevented by pre-treatment with oxidized ATP, a selective antagonist of P2X7R. Parasite killing was unlikely due to induction of nitric oxide production or cytolysis of infected macrophage, as those functions were unaltered with parasite-effective ATPe concentrations. A direct drug effect is also unlike, as ATPe enhanced axenic parasite growth. We found that leishmanial infection rendered wild-type but not P2X7R-deficient macrophages more prone to ATP-induced apoptosis. These results show that macrophage infection with L. amazonensis leads to enhanced expression of functional P2X7R, that upon ligation with ATPe helps in the elimination of the parasites by an as yet unclear mechanism possibly involving host cell apoptosis. 相似文献
12.
Bradley HJ Liu X Collins V Owide J Goli GR Smith M Surprenant A White SJ Jiang LH 《FEBS letters》2010,584(23):4740-4744
We investigated membrane targeting of the P2X7 receptor (P2X7R) in polarized epithelial cells using immunofluorescent confocal imaging. The wild-type receptor was targeted to the basolateral membrane, independently of adaptor protein μ1B. Deletion of the majority of the intracellular C-terminus, or the last 26 residues (P570-Y595), conferred targeting of the protein to the apical membrane. Alanine substitution in the microdomain P582-Q587 caused similar apical membrane targeting without major effect on the receptor function and surface expression. Our results show basolateral membrane targeting of the P2X7R in epithelial cells and that the intracellular C-terminal microdomain P582-Q587 is crucial in this process.
Structured summary
MINT-8055849:Beta-catenin (uniprotkb:B6V8E6) and P2X7R (uniprotkb:Q64663) colocalize (MI:0403) by fluorescence microscopy (MI:0416) 相似文献13.
14.
Woo CH Kim TH Choi JA Ryu HC Lee JE You HJ Bae YS Kim JH 《Biochemical and biophysical research communications》2006,351(4):972-978
Reactive oxygen species (ROS) are important regulatory molecules implicated in the signaling cascade triggered by tumor necrosis factor (TNF)alpha, although the events through which TNFalpha induces ROS generation are not well characterized. Here, we report that TNFalpha-induced ROS production was blocked by pretreatment with internalization inhibitor monodansyl cadaverine (MDC). Similarly, a transient expression of a GTP-binding and hydrolysis-defective dynamin mutant (dynamin(K44A)) that had been shown to be defective in internalization significantly attenuated the TNFalpha-induced intracellular ROS production. Importantly, the inhibition of receptor internalization suppressed TNFalpha signaling to mitogen-activated protein kinases (MAPKs) stimulation. Together, our results suggest that receptor internalization is somehow necessary for the TNFalpha-induced ROS generation and subsequent intracellular downstream signaling in non-phagocytes. 相似文献
15.
Shemon AN Sluyter R Stokes L Manley PW Wiley JS 《Biochemical and biophysical research communications》2008,365(3):515-520
A panel of 18 protein tyrosine kinase antagonists were tested for their inhibitory effect on human P2X7 receptor-mediated 86Rb+ (K+) efflux. The most potent compound (compound P), a phthalazinamine derivative and an inhibitor of vascular endothelial growth factor receptor kinase, blocked ATP-induced 86Rb+-efflux in human B-lymphocytes and erythrocytes by 76% and 66%, respectively. This inhibition was dose-dependent in both cell types with an IC50 of ∼5 μM. Kinetic analysis showed compound P was a non-competitive inhibitor of P2X7. This compound also inhibited ATP-induced ethidium+ influx into B-lymphocytes and P2X7-transfected-HEK-293 cells, as well as ATP-induced 86Rb+-efflux from canine erythrocytes. Externally, but not internally, applied compound P impaired ATP-induced inward currents in P2X7-transfected-HEK-293 cells. This study demonstrates that a novel protein tyrosine kinase antagonist directly impairs native and recombinant human P2X7 receptors. The data suggests that antagonists which target ATP-binding sites of kinases may potentially block the P2X7 receptor. 相似文献
16.
The P2X7 purinoceptor is unique amongst the P2X receptor family in that its activation is able to stimulate the release of mature,
biologically active interleukin-1β (IL-1β), as well as a variety of other proinflammatory cytokines. Coupled with the predominate
localisation of this receptor to immunocytes of haemopoetic origin, this receptor is an obvious candidate to play a major
and pivotal role in processes of pain and inflammation. Using genetically modified animals that lack the P2X7 receptor, several investigators have shown that these mice do indeed demonstrate a blunted inflammatory response, and fail
to develop pain following both inflammatory and neuropathic insult. These animals also show altered cytokine production in
response to inflammatory stimulus, which is far broader than merely modulation of IL-1β release. In this short article, we
review the role of the P2X7 receptor in modulating the release of cytokines and other mediators, and discuss the findings made from P2X7 receptor-deficient animals. As well as highlighting outstanding questions regarding this intriguing receptor, we also speculate
as to the potential therapeutic benefit of P2X7 receptor modulation. 相似文献
17.
Alloisio S Cervetto C Passalacqua M Barbieri R Maura G Nobile M Marcoli M 《FEBS letters》2008,582(28):3948-3953
The presynaptic P2X7 receptor (P2X7R) plays an important role in the modulation of transmitter release. We recently demonstrated that, in nerve terminals of the adult rat cerebral cortex, P2X7R activation induced Ca2+-dependent vesicular glutamate release and significant Ca2+-independent glutamate efflux through the P2X7R itself. In the present study, we investigated the effect of the new selective P2X7R competitive antagonist 3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methyl pyridine (A-438079) on cerebrocortical terminal intracellular calcium (intrasynaptosomal calcium concentration;[Ca2+]i signals and glutamate release, and evaluated whether P2X7R immunoreactivity was consistent with these functional tests. A-438079 inhibited functional responses. P2X7R immunoreactivity was found in about 45% of cerebrocortical terminals, including glutamatergic and non-glutamatergic terminals. This percentage was similar to that of synaptosomes showing P2X7R-mediated [Ca2+]i signals. These findings provide compelling evidence of functional presynaptic P2X7R in cortical nerve terminals. 相似文献
18.
Macrophages are unique innate immune cells that play an integral role in the defense of the host by virtue of their ability to recognize, engulf, and kill pathogens while sending out danger signals via cytokines to recruit and activate inflammatory cells. It is becoming increasingly clear that purinergic signaling events are essential components of the macrophage response to pathogen challenges and disorders such as sepsis may be, at least in part, regulated by these important sensors. The activation of the P2X7 receptor is a powerful event in the regulation of the caspase-1 inflammasome. We provide evidence that the inflammasome activation requires “priming” of macrophages prior to ATP activation of the P2X7R. Inhibition of the inflammasome activation by the tyrosine kinase inhibitor, AG126, suggests regulation by phosphorylation. Finally, the P2X7R may also be activated by other elements of the host response such as the antimicrobial peptide LL-37, which adds a new, physiologically relevant agonist to the P2X7R pathway. Therapeutic approaches to inflammation and sepsis will certainly be enhanced by an increased understanding of how purinergic receptors modulate the inflammasomes. 相似文献
19.
Lee SH Lee JG Kim JR Baek SH 《Biochemical and biophysical research communications》2007,364(4):996-1001
Although CpG containing DNA is an important regulator of innate immune responses via toll-like receptor 9 (TLR9), excessive activation of this receptor is detrimental to the host. Here, we show that cytosolic phospholipase A2 (cPLA2) activation is important for TLR9-mediated inducible nitric oxide synthase (iNOS) expression. Activation of TLR9 signaling by CpG induces iNOS expression and NO production. Inhibition of TLR9 blocked the iNOS expression and NO production. The CpG also stimulates cPLA2-hydrolyzed arachidonic acid (AA) release. Inhibition of cPLA2 activity by inhibitor attenuated the iNOS expression by CpG response. Additionally, knockdown of cPLA2 protein by miRNA also suppressed the CpG-induced iNOS expression. Furthermore, the CpG rapidly phosphorylates three MAPKs and Akt. A potent inhibitor for p38 MAPK or Akt blocked the CpG-induced AA release and iNOS expression. These results suggest that TLR9 activation stimulates cPLA2 activity via p38 or Akt pathways and mediates iNOS expression. 相似文献
20.
Kong Q Wang M Liao Z Camden JM Yu S Simonyi A Sun GY Gonzalez FA Erb L Seye CI Weisman GA 《Purinergic signalling》2005,1(4):337-347
Apoptosis is a major cause of cell death in the nervous system. It plays a role in embryonic and early postnatal brain development
and contributes to the pathology of neurodegenerative diseases. Here, we report that activation of the P2X7 nucleotide receptor (P2X7R) in rat primary cortical neurons (rPCNs) causes biochemical (i.e., caspase activation) and morphological (i.e., nuclear
condensation and DNA fragmentation) changes characteristic of apoptotic cell death. Caspase-3 activation and DNA fragmentation
in rPCNs induced by the P2X7R agonist BzATP were inhibited by the P2X7R antagonist oxidized ATP (oATP) or by pre-treatment of cells with P2X7R antisense oligonucleotide indicating a direct involvement of the P2X7R in nucleotide-induced neuronal cell death. Moreover, Z-DEVD-FMK, a specific and irreversible cell permeable inhibitor of
caspase-3, prevented BzATP-induced apoptosis in rPCNs. In addition, a specific caspase-8 inhibitor, Ac-IETD-CHO, significantly
attenuated BzATP-induced caspase-9 and caspase-3 activation, suggesting that P2X7R-mediated apoptosis in rPCNs occurs primarily through an intrinsic caspase-8/9/3 activation pathway. BzATP also induced the
activation of C-jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated kinases (ERK1/2) in rPCNs, and pharmacological
inhibition of either JNK1 or ERK1/2 significantly reduced caspase activation by BzATP. Taken together, these data indicate
that extracellular nucleotides mediate neuronal apoptosis through activation of P2X7Rs and their downstream signaling pathways involving JNK1, ERK and caspases 8/9/3. 相似文献