Molecular and functional properties of P2X receptors—recent progress and persisting challenges

Kaczmarek-Hájek, Karina; Lörinczi, Éva; Hausmann, Ralf; Nicke, Annette

doi:10.1007/s11302-012-9314-7

Cited by 197 publications

(212 citation statements)

References 575 publications

(862 reference statements)

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“…P2 receptors are activated by extracellular adenosine triphosphate (ATP) and other nucleotides [16]. In mammals, seven P2X receptor subtypes exist (P2X1–P2X7) [17]. P2X receptors are trimeric ATP-gated cation channels that mediate the rapid flux of Na + , K + , Ca 2+ , and organic ions [16,17].…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 99%

“…In mammals, seven P2X receptor subtypes exist (P2X1–P2X7) [17]. P2X receptors are trimeric ATP-gated cation channels that mediate the rapid flux of Na + , K + , Ca 2+ , and organic ions [16,17]. P2Y receptors modulate several signaling events including adenylyl cyclase, phospholipase C, and ion channel activation [16,18].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…A common topology is shared by all subtypes-two transmembrane (TM) domains, a large cysteine-rich extracellular loop, an intracellular variable C-terminus, and a N-terminus [5,13,14]. The crystal structure of zebrafish P2X4 receptor revealed a trimer in the shape of a chalice, and each subunit adopted a dolphin-like shape with two TM domains and an extracellular loop resembling the fluke and body, respectively [15,16].…”

Section: Introductionmentioning

confidence: 99%

Comparative study of the P2X gene family in animals and plants

Hou

Cao

2016

Purinergic Signalling

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P2X receptors are ligand-gated ion channels that can bind with the adenosine triphosphate (ATP) and have diverse functional roles in neuropathic pain, inflammation, special sense, and so on. In this study, 180 putative P2X genes, including 176 members in 32 animal species and 4 members in 3 species of lower plants, were identified. These genes were divided into 13 groups, including 7 groups in vertebrates and 6 groups in invertebrates and lower plants, through phylogenetic analysis. Their gene organization and motif composition are conserved in most predicted P2X members, while groupspecific features were also found. Moreover, synteny relationships of the putative P2X genes in vertebrates are conserved while simultaneously experiencing a series of gene insertion, inversion, and transposition. Recombination signals were detected in almost all of the vertebrates and invertebrates, suggesting that intragenic recombination may play a significant role in the evolution of P2X genes. Selection analysis also identified some positively selected sites that acted on the evolution of most of the predicted P2X proteins. The phenomenon of alternative splicing occurred commonly in the putative P2X genes of vertebrates. This article explored in depth the evolutional relationship among different subtypes of P2X genes in animal and plants and might serve as a solid foundation for deciphering their functions in further studies.

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“…They assemble into trimeric ligandgated cation-permeable ion channel complexes that can be activated by extracellular adenosine 5′-triphosphate (ATP) (for review, see [1,2]). The P2X7 receptor, predominantly expressed in cells of hematopoietic lineages, including macrophages, lymphocytes and microglia, seems to be the most divergent member of the P2X receptor family in terms of its individual structure, pharmacology and function [3,4].…”

Section: Introductionmentioning

confidence: 99%

Natural compounds with P2X7 receptor-modulating properties

Fischer

Urban

Immig

et al. 2013

Purinergic Signalling

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The adenosine 5′-triphosphate (ATP)-gated P2X7 receptor is a membrane-bound, non-selective cation channel, expressed in a variety of cell types. The P2X7 senses high extracellular ATP concentrations and seems to be implicated in a wide range of cellular functions as well as pathophysiological processes, including immune responses and inflammation, release of gliotransmitters and cytokines, cancer cell growth or development of neurodegenerative diseases. In the present study, we identified natural compounds and analogues that can block or sensitize the ATP (1 mM)-induced Ca 2+ response using a HEK293 cell line stably expressing human P2X7 and fluorometric imaging plate reader technology. For instance, teniposide potently blocked the human P2X7 at sub-miromolar concentrations, but not human P2X4 or rat P2X2. A marked block of ATPinduced Ca 2+ entry and Yo-Pro-1 uptake was also observed in human A375 melanoma cells and mouse microglial cells, both expressing P2X7. On the other hand, agelasine (AGL) and garcinolic acid (GA) facilitated the P2X7 response to ATP in all three cell populations. GA also enhanced the YO-PRO-1 uptake, whereas AGL did not affect the ATP-stimulated intracellular accumulation of this dye. According to the pathophysiological role of P2X7 in various diseases, selective modulators may have potential for further development, e.g. as neuroprotective or antineoplastic drugs.

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Molecular and functional properties of P2X receptors—recent progress and persisting challenges

Cited by 197 publications

References 575 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

Comparative study of the P2X gene family in animals and plants

Natural compounds with P2X7 receptor-modulating properties

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