Recommended tool compounds and drugs for blocking P2X and P2Y receptors

Müller, Christian; Namasivayam, Vigneshwaran

doi:10.1007/s11302-021-09813-7

Cited by 27 publications

(15 citation statements)

References 96 publications

(141 reference statements)

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“…The slowly hydrolyzable ATP analog ATPγS [ 7 , 20 ] (Sigma Aldrich, St. Louis, MO, USA) as well as the suramin analog NF340 [ 7 , 10 , 13 , 21 ] (Santa Cruz, Dallas, TX, USA) served as P2Y 11 receptor agonist (20 µM) and antagonist (20 µM), respectively. Further reagents utilized in this study include the PDE4-selective inhibitor rolipram (10 µM) (Sigma-Aldrich), BAPTA-AM (10 µM) (Sigma-Aldrich), calphostin C (250 nM) (Tocris), recombinant IL-1α and IL-1β (0.5–2 ng·ml −1 ) (R&D Systems, Minneapolis, MN, USA), the TACE/ADAM17 inhibitor TAPI-1 (20 µM) (Tocris), the selective inhibitor of Epac1 (R)-CE3F4 (20 µM) (Tocris), and the humanized anti-VEGF monoclonal antibody bevacizumab (0.5 µg ml −1 ) (Selleckchem, Houston, TX, USA).…”

Section: Methodsmentioning

confidence: 99%

The P2Y11 receptor of human M2 macrophages activates canonical and IL-1 receptor signaling to translate the extracellular danger signal ATP into anti-inflammatory and pro-angiogenic responses

Klaver

Gander

Dobler

et al. 2022

Cell. Mol. Life Sci.

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The cytoprotective ATP receptor P2Y 11 is upregulated during M2 macrophage differentiation and contributes to the anti-inflammatory properties of this macrophage subset. Here, we studied P2Y 11 -induced reprogramming of human M2 macrophages at the level of mRNA and protein expression. Upregulation of IL-1 receptor (IL-1R) and its known downstream effectors VEGF, CCL20 and SOCS3 as well as downregulation of the ATP-degrading ecto-ATPase CD39 emerged as hallmarks of P2Y 11 activation. The anti-inflammatory signature of the P2Y 11 transcriptome was further characterized by the downregulation of P2RX7, toll-like receptors and inflammasome components. P2Y 11 -induced IL-1R upregulation formed the basis for reinforced IL-1 responsiveness of activated M2 macrophages, as IL-1α and IL-1ß each enhanced P2Y 11 -induced secretion of VEGF and CCL20 as well as the previously reported shedding of soluble tumor necrosis factor receptor 2 (sTNFR2). Raising intracellular cyclic AMP (cAMP) in M2 macrophages through phosphodiesterase 4 inhibition enhanced P2Y 11 -driven responses. The cAMP-binding effector, exchange protein activated by cAMP 1 (Epac1), which is known to induce SOCS3, differentially regulated the P2Y 11 /IL-1R response because pharmacological Epac1 inhibition enhanced sTNFR2 and CCL20 release, but had no effect on VEGF secretion. In addition to cAMP, calcium and protein kinase C participated in P2Y 11 signaling. Our study reveals how P2Y 11 harnesses canonical and IL-1R signaling to promote an anti-inflammatory and pro-angiogenic switch of human M2 macrophages, which may be controlled in part by an Epac1-SOCS3 axis. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-022-04548-z.

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Section: Methodsmentioning

confidence: 99%

The P2Y11 receptor of human M2 macrophages activates canonical and IL-1 receptor signaling to translate the extracellular danger signal ATP into anti-inflammatory and pro-angiogenic responses

Klaver

Gander

Dobler

et al. 2022

Cell. Mol. Life Sci.

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“…A number of new compounds targeting P2X and P2Y receptors are currently under development. Of these, Cangrelor an anti-platelet nucleotide analogue drug, derived from ATP, capable of acting as a high-potency competitive analogue for most P2Y receptor subtypes (233), also scored highly in computer models seeking potential candidates to inhibit the desirable target Mpro (234). Similarly, Entecavir Hydrate, a guanosine analogue possessing anti-HBV activity was a P2X7 antagonist that could ameliorate platelet activation and thrombus formation (235).…”

Section: Discussionmentioning

confidence: 99%

The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2

2022

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A long-shared evolutionary history is congruent with the multiple roles played by purinergic signaling in viral infection, replication and host responses that can assist or hinder viral functions. An overview of the involvement of purinergic signaling among a range of viruses is compared and contrasted with what is currently understood for SARS-CoV-2. In particular, we focus on the inflammatory and antiviral responses of infected cells mediated by purinergic receptor activation. Although there is considerable variation in a patient’s response to SARS-CoV-2 infection, a principle immediate concern in Coronavirus disease (COVID-19) is the possibility of an aberrant inflammatory activation causing diffuse lung oedema and respiratory failure. We discuss the most promising potential interventions modulating purinergic signaling that may attenuate the more serious repercussions of SARS-CoV-2 infection and aspects of their implementation.

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“…This is particularly true for the subject of this review, the P2X1 receptor. Although the P2X1 receptor has been discussed in several exemplar reviews [4][5][6][7][8][9], it has often been overlooked in favour of other P2X subtypes. Herein, we review what is known about the P2X1 receptor as a drug target and the currently available ligands that target the receptor.…”

Section: P2 Receptorsmentioning

confidence: 99%

The P2X1 receptor as a therapeutic target

Bennetts

Mobbs

Ventura

et al. 2022

Purinergic Signalling

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Within the family of purinergic receptors, the P2X1 receptor is a ligand-gated ion channel that plays a role in urogenital, immune and cardiovascular function. Specifically, the P2X1 receptor has been implicated in controlling smooth muscle contractions of the vas deferens and therefore has emerged as an exciting drug target for male contraception. In addition, the P2X1 receptor contributes to smooth muscle contractions of the bladder and is a target to treat bladder dysfunction. Finally, platelets and neutrophils have populations of P2X1 receptors that could be targeted for thrombosis and inflammatory conditions. Drugs that specifically target the P2X1 receptor have been challenging to develop, and only recently have small molecule antagonists of the P2X1 receptor been available. However, these ligands need further biological validation for appropriate selectivity and drug-like properties before they will be suitable for use in preclinical models of disease. Although the atomic structure of the P2X1 receptor has yet to be determined, the recent discovery of several other P2X receptor structures and improvements in the field of structural biology suggests that this is now a distinct possibility. Such efforts may significantly improve drug discovery efforts at the P2X1 receptor.

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Recommended tool compounds and drugs for blocking P2X and P2Y receptors

Cited by 27 publications

References 96 publications

The P2Y11 receptor of human M2 macrophages activates canonical and IL-1 receptor signaling to translate the extracellular danger signal ATP into anti-inflammatory and pro-angiogenic responses

The P2Y11 receptor of human M2 macrophages activates canonical and IL-1 receptor signaling to translate the extracellular danger signal ATP into anti-inflammatory and pro-angiogenic responses

The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2

The P2X1 receptor as a therapeutic target

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