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Zhenhua Ji, Yuting Xie, Yu Guan, Yujian Zhang, Kin-Sang Cho, Min Ji, Yongping You
Previous studies have demonstrated that activation of P2X7 receptors (P2X7 R) results in the proliferation and migration of some types of tumor. Here, we asked whether and how the activated P2X7 R contribute to proliferation and migration of human glioma cells. Results showed that the number of P2X7 R positive cells was increasing with grade of tumor. In U87 and U251 human glioma cell lines, both expressed P2X7 R and the expression was enhanced by 3'-O-(4-benzoylbenzoyl) ATP (BzATP), the agonist of P2X7 R, and siRNA...
2018: BioMed Research International
Ruiting Li, Jing Wang, Ruifang Li, Fangfang Zhu, Wenjuan Xu, Gan Zha, Guangzhen He, Huan Cao, Yimin Wang, Jiong Yang
The ATP/P2X7 axis of dendritic cells (DCs) mediates the activation of NLRP3 inflammasome and promotes secretion of interleukin (IL)-1β and IL-18 to induce T helper (Th) 2, Th17 differentiation in the pathogenesis of asthma. NLRP3 inflammasome also regulates high mobility protein 1 (HMGB1) release in DCs. Recent studies demonstrated the correlation between HMGB1 expression and airway inflammation and hyper-responsiveness (AHR) in asthma. However, the relationship between the ATP/P2X7-NLRP3 axis and HMGB1 in DCs in asthma is still unclear...
March 12, 2018: Experimental Cell Research
A M Rodrigues, R S Serralha, C Farias, G R Punaro, M J S Fernandes, Elisa Mieko Suemitsu Higa
Diabetes mellitus is characterized by increased levels of reactive oxygen species (ROS), leading to high levels of adenosine triphosphate (ATP) and the activation of purinergic receptors (P2X7 ), which results in cell death. Klotho was recently described as a modulator of oxidative stress and as having anti-apoptotic properties, among others. However, the roles of P2X7 and klotho in the progression of diabetic nephropathy are still unclear. In this context, the aim of the present study was to characterize P2X7 and klotho in several stages of diabetes in rats...
March 14, 2018: Purinergic Signalling
Hanaa Safya, Amine Mellouk, Julie Legrand, Sylvain M Le Gall, Mohcine Benbijja, Colette Kanellopoulos-Langevin, Jean M Kanellopoulos, Pierre Bobé
A previous report has shown that regulatory T cells (Treg) were markedly more sensitive to adenosine-5'-triphosphate (ATP) than conventional T cells (Tconv). Another one has shown that Tregs and CD45RBlow Tconvs, but not CD45RBhigh Tconvs, displayed similar high sensitivity to ATP. We have previously reported that CD45RBlow Tconvs expressing B220/CD45RABC molecules in a pre-apoptotic stage are resistant to ATP stimulation due to the loss of P2X7 receptor (P2X7R) membrane expression. To gain a clearer picture on T-cell sensitivity to ATP, we have quantified four different cellular activities triggered by ATP in mouse T cells at different stages of activation/differentiation, in correlation with levels of P2X7R membrane expression...
2018: Frontiers in Immunology
Rebecca C Allsopp, Sudad Dayl, Anfal Bin Dayel, Ralf Schmid, Richard J Evans
P2X7 receptor (P2X7Rs) activation requires ~ 100 fold higher concentrations of ATP than other P2XR subtypes. Such high levels are found during cellular stress and P2X7Rs consequently contribute to a range of pathophysiological conditions. We have used chimeric and mutant P2X7Rs, coupled with molecular modelling, to produce a validated model of the binding mode of the subtype selective antagonist A438079 at an inter-subunit allosteric site. Within the allosteric site large effects on antagonist action were found for point mutants of residues, F88A, D92A, F95A and F103A that were conserved or similar between sensitive/insensitive P2XR subtypes suggesting that these side chain interactions were not solely responsible for high affinity antagonist binding...
March 13, 2018: Molecular Pharmacology
Mohammed Alotaibi
AIMS: Given the importance of ATP in the control of uterine activity for successful labor and involution, this study was performed to measure the level of P2X7 receptors (P2X7Rs) in rat myometrium at different gestational stages and to investigate the mechanisms of ATP-induced uterine contraction. MATERIALS AND METHODS: Myometrial tissues were obtained from rats at different gestational stages and the level of P2X7Rs was measured by ELISA. In other experiments, the effect of 1 mM ATP was applied on spontaneous contraction and the underlying mechanisms were investigated...
March 7, 2018: Life Sciences
Ivana Novak, Anna Solini
Type 2 diabetes is reaching an alarming prevalence worldwide. Its complex pathogenesis certainly includes a pivotal role of low-grade inflammation, which could be triggered by excessive purinergic signaling. In this complex scenario, extracellular ATP impairs the function of two key players: β-cell and adipose tissue. In the former, P2Y and possibly some P2X receptors-ion channels regulate insulin secretion, but it is still debated whether excessive ATP can via P2X receptors impair β-cell function directly or whether cell damage is due to an excessive systemic release of cytokines...
March 6, 2018: Current Opinion in Immunology
José R Lemos, Edward E Custer, Sonia Ortiz-Miranda
Many different types of purinergic receptors are present in the Hypothalamic-Neurohypophysial System (HNS), which synthesizes and releases vasopressin and oxytocin. The specific location of purinergic receptor subtypes has important functional repercussions for neuronal activity and synaptic output. Yet, until the advent of receptor KOs, this had been hindered by the low selectivity of the available pharmacological tools. The HNS offers an excellent opportunity to differentiate the functional properties of these purinergic receptors in cell bodies vs...
March 7, 2018: Journal of Neuroendocrinology
Carolina Paredes, Shuo Li, Xiaoli Chen, Claudio Coddou
Paralichthys olivaceus P2X7 receptor (poP2X7R) is a recently identified as a P2X7 purinergic receptor involved in innate immunity of the Japanese flounder Paralichthys olivaceus . Divalent metals are allosteric modulators of mammalian P2XRs, but there is no information for fish P2XRs. Here, we characterized the effects of divalent metals on poP2X7R channel activity by electrophysiology and molecular biology techniques. Copper, zinc and mercury inhibited poP2X7R-mediated currents with different maximal inhibition potency, while cadmium had no effect on poP2X7R activity...
March 2018: FEBS Open Bio
Wei Zhang, Biao Zhong, Chi Zhang, Congfeng Luo, Yulin Zhan
Inflammatory cytokines commonly initiate extreme changes in the synovium and cartilage microenvironment of osteoarthritis (OA) patients, which subsequently cause cellular dysfunction, especially in chondrocytes. It has been reported that induction of the purinergic P2X7 receptor (P2X7R) can regulate the expression of a variety of inflammatory factors, including interleukin (IL)-6 and -8, leading to OA pathogenesis. However, knowledge of the mechanism of upregulation of P2X7R in OA is still incomplete, and its role in chondrocyte proliferation is also not clear...
March 2018: FEBS Open Bio
J Wang-Fang, J Chun-Jie, G Fei, L Jia-Hui, L Ming
ATP (Adenosine triphosphate) is an important endogenous damage - associated molecular pattern (DAMP). P2X7 R is an ATP-gated cation channel. ATP-P2X7 R plays a vital role in the pathophysiology of many diseases because P2X7 R is distributed on various immune cells. ATP-P2X7 R signal transduction pathway has been implicated to participate in the body's immune defense against pathogens. This paper reviews the recent progress regarding ATP-P2X7 R and its effects on parasitic diseases.
July 24, 2017: Zhongguo Xue Xi Chong Bing Fang Zhi za Zhi, Chinese Journal of Schistosomiasis Control
Brandon H Kim, Alexey Pereverzev, Shuying Zhu, Abby Oi Man Tong, S Jeffrey Dixon, Peter Chidiac
Parathyroid hormone (PTH) activates the PTH/PTH-related peptide receptor (PTH1R) on osteoblasts and other target cells. Mechanical stimulation of cells, including osteoblasts, causes release of nucleotides such as ATP into the extracellular fluid. In addition to its role as an energy source, ATP serves as an agonist at P2 receptors and an allosteric regulator of many proteins. We investigated the effects of concentrations of extracellular ATP, comparable to those that activate low affinity P2X7 receptors, on PTH1R signaling...
March 1, 2018: Cellular Signalling
Nishkantha Arulkumaran, Marije L Sixma, Sean Pollen, Elias Ceravola, Elisa Jentho, Maria Prendecki, Paul S Bass, Frederick W K Tam, Robert J Unwin, Mervyn Singer
Sepsis is a major clinical problem associated with significant organ dysfunction and high mortality. The ATP-sensitive P2X7 receptor activates the NLRP3 inflammasome and is a key component of the innate immune system. We used a fluid-resuscitated rat model of fecal peritonitis and acute kidney injury (AKI) to investigate the contribution of this purinergic receptor to renal dysfunction in sepsis. Six and 24 h time-points were chosen to represent early and established sepsis, respectively. A selective P2X7 receptor antagonist (A-438079) dissolved in dimethyl sulfoxide (DMSO) was infused 2 h following induction of sepsis...
March 2018: Physiological Reports
Ning Wang, Ankita Agrawal, Niklas Rye Jørgensen, Alison Gartland
Post-menopausal osteoporosis is a condition that affects millions worldwide and places a huge socio-economic burden on society. Previous research has shown an association of loss of function SNPs in the gene for the purinergic receptor P2X7R with low bone mineral density, increased rates of bone loss and vertebral fractures in post-menopausal women. In this study we use a mouse model of oestrogen deficiency-induced bone loss and the BALB/cJ P2X7R-/- to show that absence of the P2X7R resulted in increased bone loss...
February 22, 2018: Scientific Reports
O Kambur, M A Kaunisto, B S Winsvold, T Wilsgaard, A Stubhaug, J A Zwart, E Kalso, C S Nielsen
P2X7 is a non-selective cation channel activated by extracellular ATP. P2X7 activation contributes to the pro-inflammatory response to injury or bacterial invasion and mediates apoptosis. Recently, P2X7 function has been linked to chronic inflammatory and neuropathic pain. P2X7 may contribute to pain modulation both by effects on peripheral tissue injury underlying clinical pain states, and through alterations in central nervous system processing, as suggested by animal models. To further test its role in pain sensitivity, we examined whether variation within the P2RX7 gene, which encodes the P2X7 receptor, was associated with experimentally induced pain in human patients...
February 20, 2018: Pain
Federico Colombo, Mattia Bastoni, Annamaria Nigro, Paola Podini, Annamaria Finardi, Giacomo Casella, Menon Ramesh, Cinthia Farina, Claudia Verderio, Roberto Furlan
Microvesicles (MVs) are membrane particles of 200-500 nm released by all cell types constitutively. MVs of myeloid origin are found increased in the cerebrospinal fluid (CSF) of patients suffering from neuroinflammatory disorders, although the factors triggering their production have never been defined. Here, we report that both pro- and anti-inflammatory cytokines, specifically interferon-γ and interleukin-4, are equally able to stimulate the production of MVs from microglia cells and monocytes. Additionally, we found this process to be independent from the best characterized molecular pathway so far described for membrane shedding, which is centered on the purinergic receptor P2X7, whose activation by high concentrations of extracellular ATP (exATP) results in membrane blebbing operated by the secreted enzyme acid sphingomyelinase (ASMase)...
2018: Frontiers in Immunology
Luiz E B Savio, Paola de Andrade Mello, Cleide Gonçalves da Silva, Robson Coutinho-Silva
Under physiological conditions, adenosine triphosphate (ATP) is present at low levels in the extracellular milieu, being massively released by stressed or dying cells. Once outside the cells, ATP and related nucleotides/nucleoside generated by ectonucleotidases mediate a high evolutionary conserved signaling system: the purinergic signaling, which is involved in a variety of pathological conditions, including inflammatory diseases. Extracellular ATP has been considered an endogenous adjuvant that can initiate inflammation by acting as a danger signal through the activation of purinergic type 2 receptors-P2 receptors (P2Y G-protein coupled receptors and P2X ligand-gated ion channels)...
2018: Frontiers in Pharmacology
Jiraporn Ousingsawat, Podchanart Wanitchakool, Rainer Schreiber, Karl Kunzelmann
Pyroptosis is a highly inflammatory form of programmed cell death that is caused by infection with intracellular pathogens and activation of canonical or noncanonical inflammasomes. The purinergic receptor P2X7 is activated by the noncanonical inflammasome and contributes essentially to pyroptotic cell death. The Ca2+ activated phospholipid scramblase and ion channel TMEM16F has been shown earlier to control cellular effects downstream of purinergic P2X7 receptors that ultimately lead to cell death. As pyroptotic cell death is accompanied by an increases in intracellular Ca2+ , we asked whether TMEM16F is activated during pyroptosis...
February 20, 2018: Cell Death & Disease
Gaia Pasqualetto, Andrea Brancale, Mark T Young
P2X receptors are trimeric eukaryotic ATP-gated cation channels. Extracellular ATP-their physiological ligand-is released as a neurotransmitter and in conditions of cell damage such as inflammation, and substantial evidence implicates P2X receptors in diseases including neuropathic pain, cancer, and arthritis. In 2009, the first P2X crystal structure, Danio rerio P2X4 in the apo - state, was published, and this was followed in 2012 by the ATP-bound structure. These structures transformed our understanding of the conformational changes induced by ATP binding and the mechanism of ligand specificity, and enabled homology modeling of mammalian P2X receptors for ligand docking and rational design of receptor modulators...
2018: Frontiers in Pharmacology
Linyu Wei, Sharifah A Syed Mortadza, Jing Yan, Libin Zhang, Lu Wang, Yaling Yin, Chaokun Li, Sylvie Chalon, Patrick Emond, Catherine Belzung, Dongliang Li, Chengbiao Lu, Sebastien Roger, Lin-Hua Jiang
Mood disorders are a group of psychiatric conditions that represent leading global disease burdens. Increasing evidence from clinical and preclinical studies supports that innate immune system dysfunction plays an important part in the pathophysiology of mood disorders. P2X7 receptor, belonging to the ligand-gated ion channel P2X subfamily of purinergic P2 receptors for extracellular ATP, is highly expressed in immune cells including microglia in the central nervous system (CNS) and has a vital role in mediating innate immune response...
February 14, 2018: Neuroscience and Biobehavioral Reviews
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