Pharmacology and structure of P2Y receptors

Kügelgen, Ivar von; Hoffmann, Kristina

doi:10.1016/j.neuropharm.2015.10.030

Cited by 199 publications

(191 citation statements)

References 247 publications

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“…2c) and UDP (Fig. 2e) treatments, with a Ca 2+ response to doses as low as 500 nM, compatible with the activation of P2Y2R, P2Y4R, and P2Y6 [46]. The presence of 100 μM POM-1 completely inhibited such responses (Fig.…”

Section: Pom-1 Inhibits Free Intracellular Ca 2+ Increase Induced By supporting

confidence: 52%

POM-1 inhibits P2 receptors and exhibits anti-inflammatory effects in macrophages

Pimenta-dos-Reis

Torres

Quintana

et al. 2017

Purinergic Signalling

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Extracellular nucleotides can modulate the immunological response by activating purinergic receptors (P2Rs) on the cell surface of macrophages, dendritic, and other immune cells. In particular, the activation of P2X7R can induce release of cytokines and cell death as well as the uptake of large molecules through the cell membrane by a mechanism still poorly understood. Polyoxotungstate-1 (POM-1) has been proposed as a potent inhibitor of ecto-nucleotidases, enzymes that hydrolyze extracellular nucleotides, regulating the activity of P2Rs. However, the potential impact of POM-1 on P2Rs has not been evaluated. Here, we used fluorescent dye uptake, cytoplasmic free Ca 2+ concentration measurement, patch-clamp recordings, scanning electron microscopy, and quantification of inflammatory mediators to investigate the effects of POM-1 on P2Rs of murine macrophages. We observed that POM-1 blocks the P2YR-dependent cytoplasmic Ca 2+ increase and has partial effects on the cytoplasmic Ca 2+ , increasing dependence on P2XRs. POM-1 can inhibit the events related with ATP-dependent inflammasome activation, anionic dye uptake, and also the opening of large conductance channels, which are associated with P2X7R-dependent pannexin-1 activation. On the other hand, this compound has no effects on cationic fluorescent dye uptake, apoptosis, and bleb formation, also dependent on P2X7R. Moreover, POM-1 can be considered an anti-inflammatory compound, because it prevents TNF-α and nitric oxide release from LPStreated macrophages.

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Section: Pom-1 Inhibits Free Intracellular Ca 2+ Increase Induced By supporting

confidence: 52%

POM-1 inhibits P2 receptors and exhibits anti-inflammatory effects in macrophages

Pimenta-dos-Reis

Torres

Quintana

et al. 2017

Purinergic Signalling

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“…P2X receptors are trimeric, ligandgated ion channels; whereas P2Y receptors are 7 transmembrane spanning G-protein coupled proteins (for recent reviews, see [19][20][21]). So far, 7 P2X subunits (P2X1-7) and 8 P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) have been identified, including receptors whose ligands are pyrimidines and purines [22].…”

mentioning

confidence: 99%

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Martinez-Ramirez

Dı́az-Muñoz

Butanda-Ochoa

et al. 2016

Purinergic Signalling

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The epithelium-mesenchymal transition (EMT) is an important process of cell plasticity, consisting in the loss of epithelial identity and the gain of mesenchymal characteristics through the coordinated activity of a highly regulated informational program. Although it was originally described in the embryonic development, an important body of information supports its role in pathology, mainly in cancerous and fibrotic processes. The purinergic system of inter-cellular communication, mainly based in ATP and adenosine acting throughout their specific receptors, has emerged as a potent regulator of the EMT in several pathological entities. In this context, cellular signaling associated to purines is opening the understanding of a new element in the complex regulatory network of this phenotypical differentiation process. In this review, we have summarized recent information about the role of ATP and adenosine in EMT, as a growing field with high therapeutic potential.Keywords P2 receptors . P1 receptors . Purinergic signaling . Cell migration . EMTThe purinergic system of intercellular communication General aspects The term purine (from: pure urine) was created more than 130 years ago by Emil Fischer after detailed analytical characterization of the uric acid molecule [1]. Purine molecular structure is the result of fusing pyrimidine and imidazole rings, and it exists as four N-H tautomeric forms [2]. Tautomerism of purine bases in DNA is one of the earliest reasons for mutations [3][4][5]. The interconversion of the different adenine or guanine tautomers produced mispairing with pyrimidines (which also show tautomeric forms) that may lead to changes in DNA sequence [6].Purine molecules appeared very early in the history of our planet, in the period known as Borganic evolution^, before the establishment of living systems. It has been postulated that purines could be formed by a eutectic (denoting a mixture of substances in fixed proportions that melts and freezes at a single temperature that is lower than the melting points of any of the separate constituents) concentration of HCN at extremely low temperature over a period of dozens of years [7]. Purine molecules, such as adenine and guanine, are components of the genetic material (DNA and RNA) of all living beings. Purine and pyrimidine tautomeric equilibria in nucleic acids was postulated to be significant in events such as DNA replication and repair as well as in the occurrence of point mutations [8].As nucleosides and nucleotides, purines play other highly strategic roles, acting as energy intermediates, allosteric regulators of key metabolic activities, redox molecules, and chemical messengers for signal transduction events. The two most important purines serving as extracellular ligands for paracrine and autocrine signaling are ATP and its dephosphorylated form, adenosine (ADO). ATP and ADO act as intracellular intermediate metabolites, and their presence in the

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“…P2Y2 is present on neural, bone, epithelial, endothelial, immune and renal cell types [12]. P2Y2 is activated by UTP and ATP, and to a lesser extent ATPγS [13]. Furthermore, there are synthetic P2Y2 agonists including PSB1114, MRS2698 and INS37217 [13], and synthetic P2Y2/P2Y4 agonists such as Diquafosol (INS365), which is used clinically to treat dry eye [6].…”

Section: Introductionmentioning

confidence: 99%

“…P2Y2 is activated by UTP and ATP, and to a lesser extent ATPγS [13]. Furthermore, there are synthetic P2Y2 agonists including PSB1114, MRS2698 and INS37217 [13], and synthetic P2Y2/P2Y4 agonists such as Diquafosol (INS365), which is used clinically to treat dry eye [6]. P2Y2 can be inhibited by broad-spectrum antagonists including Reactive Blue 2 and suramin [13], and by specific antagonists, such as AR-C 118925XX [6].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, there are synthetic P2Y2 agonists including PSB1114, MRS2698 and INS37217 [13], and synthetic P2Y2/P2Y4 agonists such as Diquafosol (INS365), which is used clinically to treat dry eye [6]. P2Y2 can be inhibited by broad-spectrum antagonists including Reactive Blue 2 and suramin [13], and by specific antagonists, such as AR-C 118925XX [6]. This review aims to describe in detail the roles of extracellular nucleotides and P2 receptors in the shedding of various cell surface molecules and the mechanisms involved in this process.…”

Section: Introductionmentioning

confidence: 99%

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Roles of extracellular nucleotides and P2 receptors in ectodomain shedding

Pupovac

Sluyter

2016

Cell. Mol. Life Sci.

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Ectodomain shedding of integral membrane receptors results in the release of soluble molecules and modification of the transmembrane portions to mediate or modulate extracellular and intracellular signalling. Ectodomain shedding is stimulated by a variety of mechanisms, including the activation of P2 receptors by extracellular nucleotides. This review describes in detail the roles of extracellular nucleotides and P2 receptors in the shedding of various cell surface molecules, including amyloid precursor protein, CD23, CD62L, and members of the epidermal growth factor, immunoglobulin and tumour necrosis factor families. This review discusses the mechanisms involved in P2 receptor-mediated shedding, demonstrating central roles for the P2 receptors, P2X7 and P2Y2, and the sheddases, ADAM10 and ADAM17, in this process in a number of cell types.

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Pharmacology and structure of P2Y receptors

Cited by 199 publications

References 247 publications

POM-1 inhibits P2 receptors and exhibits anti-inflammatory effects in macrophages

POM-1 inhibits P2 receptors and exhibits anti-inflammatory effects in macrophages

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Roles of extracellular nucleotides and P2 receptors in ectodomain shedding

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