Activation and Regulation of Purinergic P2X Receptor Channels

Coddou, Claudio; Yan, Zonghe; Obšil, Tomáš; Huidobro‐Toro, J. Pablo; Stojilković, Stanko S.

doi:10.1124/pr.110.003129

Cited by 433 publications

(550 citation statements)

References 537 publications

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“…Both levels of subunit expression and receptor composition vary according to cell type and brain region. ATPaffinity and receptor function are also modulated by phosphorylation state and a host of allosteric and non-allosteric modulators, including heavy metals and reactive oxygen species (Coddou et al, 2011).…”

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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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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“…After this activation process, the P2X1 and P2X3 receptor subtypes undergo rapid desensitization, while the P2X2, P2X4 and P2X7 subtypes desensitize slowly [13]. Since P2X receptor activity is involved in a number of physiological processes (regulation of cell cycle, muscle cell contraction, platelet aggregation, nociception and inflammation), they are considered as therapeutic targets for several conditions including cancer and inflammatory, neurological, cardiovascular and endocrine diseases [3,5,[14][15][16][17][18][19][20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

Ben

Marchenkova

Thomas

et al. 2016

Purinergic Signalling

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Blocking membrane currents evoked by the activation of purinergic P2X3 receptors localized on nociceptive neurons represents a promising strategy for the development of agents useful for the treatment of chronic pain conditions. Among compounds endowed with such antagonistic action, 2′,3′-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) is an ATP analogue, whose inhibitory activity on P2X receptors has been previously reported. Based on the results of molecular modelling studies performed with homology models of the P2X3 receptor, novel adenosine nucleotide analogues bearing cycloalkyl or arylalkyl substituents replacing the trinitrophenyl moiety of TNP-ATP were designed and synthesized. These new compounds were functionally evaluated on native P2X3 receptors from mouse trigeminal ganglion (TG) sensory neurons using patch clamp recordings under voltage clamp configuration. Our data show that some of these molecules are potent (nanomolar range) and reversible inhibitors of P2X3 receptors, without any apparent effect on trigeminal GABA A and 5-HT 3 receptors, whose membrane currents were unaffected by the tested compounds.

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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%

“…Besides its large size (595 amino acids) and long cytoplasmic C terminus that may interact with other signalling proteins, activation of this subtype requires rather high concentrations of extracellular ATP. The channel activity is poorly desensitising, and prolonged or repeated exposure to ATP typically results in a pore formation, allowing large organic cations to enter the cell and eventually triggering cell death [1,5]. Several mechanisms have been proposed for the channelto-pore transition, which may be caused by intrinsic properties of P2X7 or by P2X7-associated proteins ( [6] and references therein).…”

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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Activation and Regulation of Purinergic P2X Receptor Channels

Cited by 433 publications

References 537 publications

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

Natural compounds with P2X7 receptor-modulating properties

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