Roles of extracellular nucleotides and P2 receptors in ectodomain shedding

Pupovac, Aleta; Sluyter, Ronald

doi:10.1007/s00018-016-2274-2

Cited by 22 publications

(17 citation statements)

References 114 publications

(171 reference statements)

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“…Another important effect seen in many types of cells is blebbing and microvesiculation of the cell surface membrane within seconds to minutes following P2X7 activation (MacKenzie et al ., ; Verhoef et al ., ). Yet another downstream effect of P2X7 activation is the shedding of cell surface L‐selectin (CD62L) and CD23 from immune cells resulting from the stimulated proteolytic activity of ADAM10 and ADAM17 (Gu et al ., ; Pupovac and Sluyter, ). Other pro‐inflammatory effects include rapid secretion of MMP‐9 from monocytes (Gu and Wiley, ), activation of the MAP kinase pathway (Panenka et al ., ) and activation of the key transcriptional factor NF‐κB complex (Ferrari et al ., ; Korcok et al ., ).…”

Section: The P2x7 Receptor Is Best Known For Its Pro‐inflammatory Funmentioning

confidence: 99%

P2X7 as a scavenger receptor for innate phagocytosis in the brain

Wiley

2018

British J Pharmacology

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The P2X7 receptor has been widely studied for its ATP-induced pro-inflammatory effect, but in the absence of a ligand, P2X7 has a second function as a scavenger receptor, which is active in the development of the human brain. The scavenger activity of P2X7 is only evident in the absence of serum but is fully active in cerebrospinal fluid. P2X7 on the cell surface is present as a membrane complex, and an attachment to non-muscle myosin of the cytoskeleton is required for particle engulfment. Selective antagonists of P2X7 pro-inflammatory function have little effect on phagocytosis, but inheritance of a variant haplotype spanning the P2RX7 and P2RX4 genes has been associated with loss of P2X7-mediated phagocytosis. Recent studies in mice suggest that the innate phagocytosis mediated by P2X7 receptors declines with ageing. Thus, defective P2X7-mediated phagocytosis may contribute to age-related neuro-degenerative diseases including Alzheimer's disease, age-related macular degeneration and primary progressive multiple sclerosis.

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Section: The P2x7 Receptor Is Best Known For Its Pro‐inflammatory Funmentioning

confidence: 99%

P2X7 as a scavenger receptor for innate phagocytosis in the brain

Wiley

2018

British J Pharmacology

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“…P2X subunits share similar membrane topology: Intracellular N- and C-termini, two membrane-spanning domains, and an extracellular loop containing an ATP binding site (16,17). P2X7 is involved in various physiological and pathophysiological processes, including activation of the inflammasome and inflammatory factors (18), stimulation of metalloproteases (19), and the generation of reactive oxygen and nitrogen species (20). Previous studies reported that P2X7 may be a susceptibility gene in non-obese diabetic mice (21,22).…”

Section: Introductionmentioning

confidence: 99%

High glucose inhibits osteogenic differentiation and proliferation of MC3T3‑E1 cells by regulating P2X7

Yang

Zhang

2019

Mol Med Report

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Diabetes mellitus adversely affects human bones and increases the risk of developing osteoporosis. In the present study, treatment with 30 mmol/l glucose was used to establish a high glucose (HG) cell model in vitro. Plasmids were used to overexpress the P2X purinoceptor 7 (P2X7) gene. Brilliant blue G and (4-benzoyl-benzoyl)-ATP were used as a P2X7 antagonist and agonist, respectively. Proliferation of osteogenic MC3T3-E1 cells and alkaline phosphatase (ALP) activity were determined using MTT and colorimetric assays, respectively. Alizarin Red S was used to assess calcification of MC3T3-E1 cells. Western blotting and reverse transcription-quantitative PCR were performed to determine protein and mRNA expression levels. The results demonstrated that HG inhibited MC3T3-E1 cell proliferation and P2X7 expression, reduced calcification, and downregulated the expression levels of ALP and osteocalcin (Ocn) in MC3T3-E1 cells. Overexpression of P2X7 in HG conditions increased calcification and proliferation, and upregulated the levels of ALP and Ocn in MC3T3-E1 cells. Inhibition of P2X7 downregulated the expressions of ALP and Ocn in MC3T3-E1 cells under HG conditions. Therefore, the present results indicated that HG caused damage to osteogenic MC3T3-E1 cells. Thus, P2X7 may be a regulatory factor that may be used to counteract the effects of HG on osteogenesis.

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“…Multiple studies have demonstrated secretion of cytokines from the IL-1 family (IL-1b, IL-1a, IL-18) in response to P2X7dependent activation of the NLRP3-caspase-1 inflammasome (Giuliani et al, 2017). Other cytokines such as those relying on cleavage by metalloproteinases (e.g., TNF-a) are also released following P2X7 activation as well as other cell surface proteins (e.g., L-selectin, VCAM-1, CD23, and CD14) which are shed (Pupovac and Sluyter, 2016). The particular cytokines released by P2X7 may depend on the cell type under examination, for example, in T lymphocytes, P2X7 can contribute to IL-2 production and secretion (Yip et al, 2009).…”

Section: P2x7 Receptormentioning

confidence: 99%

To Inhibit or Enhance? Is There a Benefit to Positive Allosteric Modulation of P2X Receptors?

et al. 2020

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The family of ligand-gated ion channels known as P2X receptors were discovered several decades ago. Since the cloning of the seven P2X receptors (P2X1-P2X7), a huge research effort has elucidated their roles in regulating a range of physiological and pathophysiological processes. Transgenic animals have been influential in understanding which P2X receptors could be new therapeutic targets for disease. Furthermore, understanding how inherited mutations can increase susceptibility to disorders and diseases has advanced this knowledge base. There has been an emphasis on the discovery and development of pharmacological tools to help dissect the individual roles of P2X receptors and the pharmaceutical industry has been involved in pushing forward clinical development of several lead compounds. During the discovery phase, a number of positive allosteric modulators have been described for P2X receptors and these have been useful in assigning physiological roles to receptors. This review will consider the major physiological roles of P2X1-P2X7 and discuss whether enhancement of P2X receptor activity would offer any therapeutic benefit. We will review what is known about identified compounds acting as positive allosteric modulators and the recent identification of drug binding pockets for such modulators.

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Roles of extracellular nucleotides and P2 receptors in ectodomain shedding

Cited by 22 publications

References 114 publications

P2X7 as a scavenger receptor for innate phagocytosis in the brain

P2X7 as a scavenger receptor for innate phagocytosis in the brain

High glucose inhibits osteogenic differentiation and proliferation of MC3T3‑E1 cells by regulating P2X7

To Inhibit or Enhance? Is There a Benefit to Positive Allosteric Modulation of P2X Receptors?

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