Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor

Pelegrı́n, Pablo; Surprenant, Annmarie

doi:10.1038/sj.emboj.7601378

Cited by 1,274 publications

(1,592 citation statements)

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“…The P2X7 receptor has been reported to interact with the channel protein pannexin 1 [32], and this complex creates a sizeable pore permeable to larger molecules such as ethidium bromide [33]. To assess the effect of pannexin1 on ETX-induced hemolysis, carbenoxolone and mefloquine were used as antagonists for pannexin 1.…”

Section: Resultsmentioning

confidence: 99%

Hemolysis in human erythrocytes by Clostridium perfringens epsilon toxin requires activation of P2 receptors

et al. 2018

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Epsilon-toxin (ETX) is produced by types B and D strains of Clostridium perfringens, which cause fatal enterotoxaemia in sheep, goats and cattle. Previous studies showed that only a restricted number of cell lines are sensitive to ETX and ETX-induced hemolysis has not previously been reported. In this study, the hemolytic ability of ETX was examined using erythrocytes from 10 species including murine, rabbit, sheep, monkey and human. We found that ETX caused hemolysis in human erythrocytes (HC50 = 0.2 μM) but not erythrocytes from the other test species. Moreover, the mechanism of ETX-induced hemolysis was further explored. Recent studies showed that some bacterial toxins induce hemolysis through purinergic receptor (P2) activation. Hence, the function of purinergic receptors in ETX-induced hemolysis was tested, and we found that the non-selective P2 receptor antagonists PPADS inhibited ETX-induced lysis of human erythrocytes in a concentration-dependent manner, indicating that ETX-induced hemolysis requires activation of purinergic receptors. P2 receptors comprise seven P2X (P2X1–7) and eight P2Y (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11–P2Y14) receptor subtypes. The pattern of responsiveness to more selective P2-antagonists implies that both P2Y13 and P2X7 receptors are involved in ETX-induced hemolysis in human species. Furthermore, we demonstrated that extracellular ATP is likely not involved in ETX-induced hemolysis and the activation of P2 receptors. These findings clarified the mechanism of ETX-induced hemolysis and provided new insight into the activities and ETX mode of action.

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Section: Resultsmentioning

confidence: 99%

Hemolysis in human erythrocytes by Clostridium perfringens epsilon toxin requires activation of P2 receptors

et al. 2018

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“…Reduced intracellular K þ concentration is the primary trigger of caspase-1 activation (Munoz-Planillo et al, 2013). While some reports indicate that Panx1 channel opening is an obligatory part of both NLRP1 and NLRP3 inflammasome activation (de Rivero Vaccari et al, 2008;Pelegrin and Surprenant, 2006;Silverman et al, 2009), other groups have reported P2X7 receptor-induced IL-1b release, independent of Panx1 (Pelegrin et al, 2008;Qu et al, 2011). A further study postulated that Panx1 is responsible for the release of ATP from dying cells, upstream of P2X7 activation in the signaling cascade (Dahl and Keane, 2012).…”

Section: The Role Of P2x Receptors In Neuroinflammationmentioning

confidence: 99%

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

et al. 2016

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a b s t r a c tThe principle functions of neuroinflammation are to limit tissue damage and promote tissue repair in response to pathogens or injury. While neuroinflammation has utility, pathophysiological inflammatory responses, to some extent, underlie almost all neuropathology. Understanding the mechanisms that control the three stages of inflammation (initiation, propagation and resolution) is therefore of critical importance for developing treatments for diseases of the central nervous system. The purinergic signaling system, involving adenosine, ATP and other purines, plus a host of P1 and P2 receptor subtypes, controls inflammatory responses in complex ways. Activation of the inflammasome, leading to release of pro-inflammatory cytokines, activation and migration of microglia and altered astroglial function are key regulators of the neuroinflammatory response. Here, we review the role of P1 and P2 receptors in mediating these processes and examine their contribution to disorders of the nervous system. Firstly, we give an overview of the concept of neuroinflammation. We then discuss the contribution of P2X, P2Y and P1 receptors to the underlying processes, including a discussion of cross-talk between these different pathways. Finally, we give an overview of the current understanding of purinergic contributions to neuroinflammation in the context of specific disorders of the central nervous system, with special emphasis on neuropsychiatric disorders, characterized by chronic low grade inflammation or maternal inflammation. An understanding of the important purinergic contribution to neuroinflammation underlying neuropathology is likely to be a necessary step towards the development of effective interventions.

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“…Current inhibition curves indicated IC 50 of 16.3±2.1 nM (n ¼ 3-9 cells) and 9.8±0.9 nM (n ¼ 2-9 cells) for KN62 and A740003, respectively (Figure 2d), which are the classical concentrations used for antagonizing hP2X 7 R activity (Donnelly-Roberts and Jarvis, 2007). Sustained activation of P2X 7 R is also known to induce membrane permeation following the activation of pannexin-1 and allowing the uptake of membrane-impermeant fluorescent dyes such as ethidium (Pelegrin and Surprenant, 2006). Ethidium uptake was also recorded in MDA-MB-435s cells stimulated with ATP (5mM), which was completely inhibited when KN62 (1 mM) was added to the external solution (Figure 2e).…”

Section: Human Cancer Cells Express Functional P2x 7 Rmentioning

confidence: 99%

“…PCR products were then analyzed by electrophoresis in 1% agarose gel containing ethidium bromide, and visualized by UV transillumination. Detailed methods used for qRT-PCR have been described previously (Pelegrin and Surprenant, 2006). Specific primers were purchased from Qiagen (QuantiTech Primer Assays), for each primer set the efficiency was 495% and a single product was seen on melt curve analysis.…”

Section: Reverse Transcription Pcr (Rt-pcr) and Quantitative Rt-pcr Amentioning

confidence: 99%

“…Extracellular ATP acts as a signalling molecule by activating plasma membrane G protein-coupled P2Y receptors and/or ligand-gated ion channels P2X receptors (Burnstock, 2006). Among the members of the P2X receptors family, the latest cloned P2X 7 receptors (P2X 7 R) (Rassendren et al, 1997) are very unique by different features, some of them are: (1) their sensitivity to ATP (North, 2002), (2) their facilitation under successive or sustained applications of agonist (Hibell et al, 2000;Roger et al, 2008Roger et al, , 2010a and (3) the appearance of a large, non-selective membrane pore after sustained stimulations with ATP (Pelegrin and Surprenant, 2006). Recently, several tumours have been shown to express P2X 7 R at unusually high levels (Adinolfi et al, 2002;Zhang et al, 2004;Slater et al, 2004a, b;Wang et al, 2004a;Raffaghello et al, 2006;Deli et al, 2007;Solini et al, 2008), however, their functionality and involvement in the physiology of cancer cells remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

et al. 2011

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ATP-gated P2X 7 receptors (P2X 7 R) are unusual plasma membrane ion channels that have been extensively studied in immune cells. More recently, P2X 7 R have been described as potential cancer cell biomarkers. However, mechanistic links between P2X 7 R and cancer cell processes are unknown. Here, we show, in the highly aggressive human breast cancer cell line MDA-MB-435s, that P2X 7 receptor is highly expressed and fully functional. Its activation is responsible for the extension of neurite-like cellular prolongations, of the increase in cell migration by 35% and in cell invasion through extracellular matrix by 150%. The change in cancer cell morphology and the increased migration appeared to be due to the activation of Ca 2 þ -activated SK3 potassium channels. The enhanced invasion through the extracellular matrix was related to the increase of mature forms of cysteine cathepsins in the extracellular medium, which was independent of SK3 channel activity and not associated with cell death. Pharmacological targeting of P2X 7 R in vivo was crucial for cell invasiveness in a zebrafish model of metastases. Our results demonstrate a novel mechanistic link between P2X 7 R functionality in cancer cells and invasiveness, a key parameter in tumour growth and in the development of metastases. They also suggest a potential therapeutic role for the newly developed P2X 7 R antagonists.

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Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor

Cited by 1,274 publications

References 48 publications

Hemolysis in human erythrocytes by Clostridium perfringens epsilon toxin requires activation of P2 receptors

Hemolysis in human erythrocytes by Clostridium perfringens epsilon toxin requires activation of P2 receptors

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

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