Disease relevance of P2rx7

• This report implicates the P2Z/P2X7 receptor in the control of protein kinase cascades and transcriptional processes, and these observations are likely to be important for the development of selective purinergic receptor antagonists for the treatment of septic shock [1].
• These results suggest that activation of P2X7 receptors may contribute to inflammatory responses in microglial cells seen in neurodegenerative diseases [2].
• In human and rodent macrophages, activation of the P2X7 nucleotide receptor stimulates interleukin-1beta processing and release, apoptosis, and killing of intracellular Mycobacterium tuberculosis [3].
• The P2X7 receptor is a candidate product of murine and human lupus susceptibility loci: a hypothesis and comparison of murine allelic products [4].
• P2X7 receptors regulate NKT cells in autoimmune hepatitis [5].
• Taken together, these results suggest that P2X7R affects Chlamydia infection by directly inhibiting infection in epithelial cells, rather than through the ability of P2X7R to modulate IL-1beta secretion [6].

High impact information on P2rx7

• We show here that treatment of infected macrophages with ATP leads to killing of chlamydiae through ligation of the purinergic receptor, P2X(7)R [7].
• NAD-induced T cell death: ADP-ribosylation of cell surface proteins by ART2 activates the cytolytic P2X7 purinoceptor [8].
• ART2-catalyzed ADP-ribosylation activates the cytolytic P2X7 purinoceptor, causing calcium flux, pore formation, phosphatidylserine exposure, shedding of CD62L, cell shrinkage, and propidium iodide uptake [8].
• This effect was specifically mediated by the P2Z receptor, because selective receptor antagonists prevented NF-kappaB activation [9].
• Cells of the macrophage lineage express a peculiar surface receptor for extracellular ATP, designated P2Z/P2X7 purinergic receptor, that induces pore formation and collapse of the plasma membrane potential [9].

Biological context of P2rx7

• Additionally, o-ATP prevents cell death induced by P2Z/P2X7 receptor agonists [1].
• In summary, these data suggest that the P2Z/P2X7 receptor modulates LPS-induced macrophage activation as assessed by iNOS expression and NO production [1].
• In the present study, we demonstrate that pretreatment of RAW 264.7 macrophages with a P2Z/P2X7 receptor antagonist, periodate oxidized adenosine 5'-triphosphate (o-ATP), substantially inhibits LPS-stimulated NO production and iNOS expression without altering cell viability [1].
• BzATP, a potent P2X7 receptor agonist, was more effective than ATP, ADP, or 2-MeSATP at enhancing IFN gamma-induced ERK1/2 phosphorylation [2].
• P2Z/P2X7 receptor-dependent apoptosis of dendritic cells [10].

Anatomical context of P2rx7

• To test this hypothesis, we evaluated whether antagonism of the P2Z/P2X7 receptor can influence LPS signaling and expression of the inducible form of nitric-oxide synthase (iNOS) in RAW 264.7 macrophages [1].
• Maturation and release of interleukin-1beta by lipopolysaccharide-primed mouse Schwann cells require the stimulation of P2X7 receptors [11].
• P2X7 receptor-dependent and -independent T cell death is induced by nicotinamide adenine dinucleotide [12].
• Because BzATP activates multiple P2 receptors, we examined responses of osteoclasts derived from WT and P2X7 receptor KO mice [13].
• Essential role for Ca2+ in regulation of IL-1beta secretion by P2X7 nucleotide receptor in monocytes, macrophages, and HEK-293 cells [14].

Associations of P2rx7 with chemical compounds

• Previous studies have suggested that the P2Z/P2X7 purinergic receptor can participate in nucleotide-induced modulation of lipopolysaccharide (LPS) stimulated inflammatory mediator production [1].
• This effect on LPS-induced iNOS expression is mimicked by a pyridoxal-phosphate-based antagonist (pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid) of the P2Z/P2X7 purinergic receptor, indicating that these results are not unique to o-ATP [1].
• Apoptosis could be selectively triggered by tetrabasic ATP, since other purine/pyrimidine nucleotides were ineffective, and it was mimicked by the P2Z receptor agonist, benzoylbenzoyl ATP, and blocked by magnesium and the irreversible antagonist, oxidized ATP [10].
• 2) The effect was inhibited by oxidized ATP and the isoquinoline KN-62, two known P2X7 receptor antagonists [3].
• Inhibitory effects of chloride on the activation of caspase-1, IL-1beta secretion, and cytolysis by the P2X7 receptor [15].
• P2X(7) receptor protein and BzATP-activated inward cation currents were absent, and importantly, purinergic receptor agonist-stimulated salivation was suppressed by more than 70% in submandibular glands from P2X(7)-null mice [16].
• We propose that luminal ATP accumulates in response to selected lipids and activates the P2X7R that signals across the phagosomal membrane to trigger actin assembly on the cytoplasmic membrane surface [17].

Physical interactions of P2rx7

• CONCLUSION: These findings show that P2X7 nucleotide receptors couple to activation of NF-kappaB in osteoclasts [13].

Enzymatic interactions of P2rx7

• Since the P2Z/P2X7 receptor antagonist oxidized adenosine triphosphate decreased lipopolysaccharide induced nitric oxide production, and lipopolysaccharide was able to promote ATP release from macrophage cells, it seems likely that endogenous ATP is involved in nitric oxide formation during endotoxin challenge [18].

Regulatory relationships of P2rx7

• P2X7 nucleotide receptor activation enhances IFN gamma-induced type II nitric oxide synthase activity in BV-2 microglial cells [2].
• Our data confirm the importance of the P2X7 receptor in ATP-stimulated cell death and IL-1beta release from LPS-primed macrophages [19].
• Extracellular nucleotides act through P2X7 receptors to activate NF-kappaB in osteoclasts [13].
• The P2X7 receptor (P2X7R) is an ATP-gated cation channel that activates caspase-1 leading to the maturation and secretion of IL-1beta [15].
• Thus, choline, which enters the cells through the BzATP-induced pores, can act to inhibit P2z receptor-stimulated PLD activity but not pore formation [20].
• P2X7-induced shrinkage and PS translocation depend upon K+ efflux via KCa3.1, but use a pathway of Cl- efflux distinct from that previously implicated in apoptosis [21].

Other interactions of P2rx7

• We have investigated the role of P2X7 receptor and of an associated calcium-activated potassium conductance (BK channels) in IL-1beta maturation and releasing processes by Schwann cells [11].
• The Pro-451 to Leu polymorphism within the C-terminal tail of P2X7 receptor impairs cell death but not phospholipase D activation in murine thymocytes [22].
• Secretion of intracellular IL-1 receptor antagonist (type 1) is dependent on P2X7 receptor activation [23].
• Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release [24].
• RT-PCR analysis confirmed the mRNA expression of the P2Z/P2X7 receptor and the absence of P2X1 [10].

Analytical, diagnostic and therapeutic context of P2rx7

• In this study, we investigated whether second messengers are necessary to open the pore associated with the P2X7 receptor in cells that expressed the pore activity by using the patch-clamp technique in whole cell and cell-attached configurations in conjunction with fluorescent imaging [25].
• Using immunofluorescence it was demonstrated that P2X7 protein expression, in both mouse and pig, occurs specifically in the theca cells from antral follicles [26].
• In situ hybridization using a digoxigenin-labelled riboprobe, and immunohistochemistry using an antibody raised against a C-terminal peptide sequence, were used to determine the distribution of the P2X7 receptor mRNA and protein in rat and mouse tissues and cell lines [27].
• Using this technique we have generated highly specific polyclonal (rabbit) and monoclonal (rat) anti-P2X7 antibodies that readily detect mouse P2X7 on the surface of living cells by immunofluorescence analyses and flow cytometry [28].

References