P<sub>2Z</sub>/P2X<sub>7</sub>receptor-dependent apoptosis of dendritic cells

Coutinho‐Silva, Robson; Persechini, Pedro M.; Bisaggio, Rodrigo da Cunha; Perfettini, Jean‐Luc; Neto, Ana Cristina Torres De Sa; Kanellopoulos, Jean; Motta-Ly, Iris; Dautry‐Varsat, Alice; Ojcius, David M.

doi:10.1152/ajpcell.1999.276.5.c1139

Cited by 208 publications

(169 citation statements)

References 48 publications

Supporting

Mentioning

157

Contrasting

Unclassified

Order By: Relevance

“…We also find three other bands marked by the anti-P2X 7 antibody, with lower molecular weights. In this experiment, positive control with macrophage cells, which have endogenous expression of P2X 7 homomeric receptors [11], confirms the band corresponding to the P2X 7 subunit at approximately 70 kDa. Therefore, Leydig cells endogenously express the classical P2X 7 subunits and other P2X 7 subunits probably derived from alternative splice.…”

Section: Discussionsupporting

confidence: 76%

Mouse Leydig cells express multiple P2X receptor subunits

Antonio

Costa

Gomes

et al. 2008

Purinergic Signalling

View full text Add to dashboard Cite

ATP acts on cellular membranes by interacting with P2X (ionotropic) and P2Y (metabotropic) receptors. Seven homomeric P2X receptors (P2X 1 -P2X 7 ) and seven heteromeric receptors (P2X 1/2 , P2X 1/4 , P2X 1/5 , P2X 2/3 , P2X 2/6 , P2X 4/6 , P2X 4/7 ) have been described. ATP treatment of Leydig cells leads to an increase in [Ca 2+ ] i and testosterone secretion, supporting the hypothesis that Ca 2+ signaling through purinergic receptors contributes to the process of testosterone secretion in these cells. Mouse Leydig cells have P2X receptors with a pharmacological and biophysical profile resembling P2X 2 . In this work, we describe the presence of several P2X receptor subunits in mouse Leydig cells. Western blot experiments showed the presence of P2X 2 , P2X 4 , P2X 6 , and P2X 7 subunits. These results were confirmed by immunofluorescence. Functional results support the hypothesis that heteromeric receptors are present in these cells since 0.5 μM ivermectin induced an increase (131.2±5.9%) and 3 μM ivermectin a decrease (64.2±4.8%) in the whole-cell currents evoked by ATP. These results indicate the presence of functional P2X 4 subunits. P2X 7 receptors were also present, but they were non-functional under the present conditions because dye uptake experiments with Lucifer yellow and ethidium bromide were negative. We conclude that a heteromeric channel, possibly P2X 2/4/6 , is present in Leydig cells, but with an electrophysiological and pharmacological phenotype characteristic of the P2X 2 subunit.

show abstract

Section: Discussionsupporting

confidence: 76%

Mouse Leydig cells express multiple P2X receptor subunits

Antonio

Costa

Gomes

et al. 2008

Purinergic Signalling

View full text Add to dashboard Cite

show abstract

“…A third type of receptor is the unselective pore-forming P2X7 receptor, which is activated by ATP in the millimolar range and selectively inhibited by oxyATP (28). P2X7 is involved in Ag presentation and apoptosis of murine DC (13,16). Because oxyATP was not antagonistic in our experiments, the P2X7 receptor appears not to be involved in the activation of human DC.…”

Section: Discussionmentioning

confidence: 78%

“…Recently, it has been shown that DC express P2 receptors, but their physiological role is unclear. Proposed functions include improved Ag presentation (13), cytokine production (14), chemotaxis (15), and induction of apoptosis (16).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Extracellular ATP and TNF-α Synergize in the Activation and Maturation of Human Dendritic Cells

Schnurr

Then

Galambos

et al. 2000

The Journal of Immunology

174

140

View full text Add to dashboard Cite

Extracellular ATP mediates numerous biological activities by interacting with plasma membrane P2 purinergic receptors. Recently, P2 receptors have been described on dendritic cells (DC), but their functional role remains unclear. Proposed functions include improved Ag presentation, cytokine production, chemotaxis, and induction of apoptosis. We investigated the effects of ATP and of other P2 receptor agonists on endocytosis, phenotype, IL-12 secretion, and T cell stimulatory capacity of human monocyte-derived DC. We found that in the presence of extracellular ATP, DC transiently increase their endocytotic activity. Subsequently, DC up-regulate CD86, CD54, and MHC-II; secrete IL-12; and exhibit an improved stimulatory capacity for allogeneic T cells. These effects were more pronounced when chemically modified ATP derivatives with agonistic activity on P2 receptors, which are resistent to degradation by ectonucleotidases, were applied. Furthermore, ATP and TNF-α synergized in the activation of DC. Stimulated with a combination of ATP and TNF-α, DC expressed the maturation marker CD83, secreted large amounts of IL-12, and were potent stimulators of T cells. In the presence of the P2 receptor antagonist suramin, the effects of ATP were completely abolished. Our results suggest that extracellular ATP may play an important immunomodulatory role by activating DC and by skewing the immune reaction toward a Th1 response through the induction of IL-12 secretion.

show abstract

“…In addition, stimulation of P2Y 2 receptors in C6 glioma cells (28) and/or P2Y 4 receptors in rat glomerular mesangial cells can induce proliferation (29). At present apoptosis initiated by nucleotides is known only for a P2X receptor, being a prominent consequence of P2X 7 receptor activation in human macrophages and leukocytes as well as in mesangial, dendritic, and microglial cells (30,31). As with most examples of apoptosis, the P2X 7 receptor-initiated cascade, which includes the coupling of the ion channel to the SAPK-signaling cascade (32), involves a defined sequence of phenotypic changes that culminate in death only several hours after the exposure to ATP.…”

mentioning

confidence: 99%

Adenosine Nucleotides Acting at the Human P2Y1Receptor Stimulate Mitogen-activated Protein Kinases and Induce Apoptosis

Sellers

Simon

Lundahl

et al. 2001

Journal of Biological Chemistry

104

View full text Add to dashboard Cite

For the widely distributed P2Y receptors for nucleotides, the transductional and functional responses downstream of their coupling to G proteins are poorly characterized. Here we describe apoptotic induction and the associated differential stimulation of mitogenactivated protein (MAP) kinase family members by the human P2Y 1 receptor. The potent P2Y 1 receptor agonist, 2-methylthio-ADP (2-MeSADP), stimulated the extracellular-signal regulated kinases (ERK1/2) (EC 50 ϳ5 nM) as well as several, but not all isoforms detected, of the stress-activated protein kinase (SAPK) family. Phosphoisoforms of p38 were unaffected. The induced kinase activity was blocked by the P2Y 1 receptor-selective antagonist, adenosine-2-phosphate-5-phosphate, but unaffected by pertussis toxin. In addition, the endogenous ligand ADP, and significantly also 2-MeSATP, induced concentration-dependent phosphorylation changes in the same MAP kinase family members. The sustained activation of ERK1/2 was associated with Elk-1 phosphorylation that was abolished by the MEK1 inhibitor, PD 98059. However, the concomitant transient activation of the SAPKs was not sufficient to induce c-Jun or ATF-2 phosphorylation. The transient phase of the ERK activity was partially inhibited either by the phosphatidylinositol 3-kinase inhibitor, LY 294002, or the PKC inhibitor, Gö 6976. In addition, the Src inhibitor, PP1, or expression of dominant negative Ras also attenuated the transient phase of ERK phosphorylation. In contrast, inhibition of Ras or Src had no effect on the sustained ERK activity, which was critically dependent on phosphatidylinositol 3-kinase. The transient SAPK activity was suppressed by expression of a dominant negative form of MKK4. Furthermore, this kinase-deficient mutant inhibited 2-MeSADP-induced caspase-3 stimulation and the associated decrease in cell number. In conclusion, adenosine di-and triphosphate stimulation of the human P2Y 1 receptor can transiently activate the Ras-ERK cascade via the cooperative effects of phosphatidylinositol 3-kinase, Src and PKC. The sustained ERK stimulation, via a Ras-insensitive pathway, culminates in Elk-1 activation without inducing a proliferation effect. The transient SAPK activity did not evoke transcription factor phosphorylation but was required for the P2Y 1 receptor-mediated apoptotic function.Extracellular nucleotides can interact with cell surface P2 receptors both in the central nervous system and in peripheral tissues to produce a broad range of physiological effects. The P2 family is divided into two main types as follows: the P2X receptors are ligand-gated ion channels, and the P2Y receptors are G protein-coupled (1, 2). Part of the present study describes the signaling pathways of the P2Y 1 receptor, the first member of the P2Y family to be identified (3). The P2Y 1 receptor is widely distributed and has been described in mammalian heart, vascular, liver, kidney, prostate, gastrointestinal, pulmonary, connective, and immune tissues (4, 5). It has also been identified in skeletal muscle ...

show abstract

P_2Z/P2X₇receptor-dependent apoptosis of dendritic cells

Cited by 208 publications

References 48 publications

Mouse Leydig cells express multiple P2X receptor subunits

Mouse Leydig cells express multiple P2X receptor subunits

Extracellular ATP and TNF-α Synergize in the Activation and Maturation of Human Dendritic Cells

Adenosine Nucleotides Acting at the Human P2Y1Receptor Stimulate Mitogen-activated Protein Kinases and Induce Apoptosis

Contact Info

Product

Resources

About

P2Z/P2X7receptor-dependent apoptosis of dendritic cells

Cited by 208 publications

References 48 publications

Mouse Leydig cells express multiple P2X receptor subunits

Mouse Leydig cells express multiple P2X receptor subunits

Extracellular ATP and TNF-α Synergize in the Activation and Maturation of Human Dendritic Cells

Adenosine Nucleotides Acting at the Human P2Y1Receptor Stimulate Mitogen-activated Protein Kinases and Induce Apoptosis

Contact Info

Product

Resources

About

P_2Z/P2X₇receptor-dependent apoptosis of dendritic cells