Transient up-regulation of P2Y2 nucleotide receptor mRNA expression is an immediate early gene response in activated thymocytes (original) (raw)
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Mechanisms of P2 receptor-evoked DNA synthesis in thyroid FRTL-5 cells
Journal of Cellular Physiology, 2001
The expression of the P2 receptors and their functional responses were studied in rat thyroid FRTL-5 cells. RT-PCR analysis revealed transcripts for the G proteincoupled P2Y 2 , P2Y 4 and P2Y 6 receptors, and for the transmitter-gated ion channel P2X 3 , P2X 4 and P2X 5 subunits. In Fura-2-loaded cells, UTP, ATP, ATPgS or UDP increased [Ca 2 ] i , and behaved as potent full agonists, while 2-Methylthio-ATP (2-MeSATP), a,b-methylene-ATP (a,b-meATP) and pure ADP were weak agonists. The agonist-mediated [Ca 2 ] i increases were diminished in Ca 2 -free buffer, and by pertussis toxin (PTX) or suramin treatments. ATP, UTP, UDP and ATPgS increased 3 H-thymidine incorporation into DNA and expression of the protooncogenes c-Fos and c-Jun, while 2-MeSATP was ineffective, and a,b-meATP gave a response only at 100-mM dose. The ATP-stimulated expression of c-Fos and c-Jun was dependent on Ca 2 , and protein kinase C, but not on calmodulin or Ca 2 /calmodulin-dependent protein kinase II. Extracellular signal-regulated kinases (ERK1 and ERK2) are also involved as the MEK inhibitor, PD98059, reduced both ATP-evoked 3 H-thymidine incorporation and c-Fos and c-Jun expression. These results indicate that multiple P2Y receptor subtypes and at least the P2X 5 subtype are functionally expressed in FRTL-5 cells, and that nucleotides acting via P2 receptors are involved in the regulation of DNA-synthesis.
P2Y receptors: New subtypes, new functions
Drug Development Research, 2003
The orphan receptor GPR86 was recently identified as a new ADP receptor coupled to G i and named P2Y 13 . This brings to eight the number of genuine P2Y receptors. On the basis of sequence homology, they can be subdivided into two subgroups: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 ; and P2Y 12 , P2Y 13 , and the UDP-glucose receptor that should be renamed P2Y 14 . Some pharmacological properties of the P2Y 13 receptor are significantly different from those of the P2Y 12 receptor:
P2X7 Receptor at the Crossroads of T Cell Fate
International Journal of Molecular Sciences
The P2X7 receptor is a ligand-gated, cation-selective channel whose main physiological ligand is ATP. P2X7 receptor activation may also be triggered by ARTC2.2-dependent ADP ribosylation in the presence of extracellular NAD. Upon activation, this receptor induces several responses, including the influx of calcium and sodium ions, phosphatidylserine externalization, the formation of a non-selective membrane pore, and ultimately cell death. P2X7 receptor activation depends on the availability of extracellular nucleotides, whose concentrations are regulated by the action of extracellular nucleotidases such as CD39 and CD38. The P2X7 receptor has been extensively studied in the context of the immune response, and it has been reported to be involved in inflammasome activation, cytokine production, and the migration of different innate immune cells in response to ATP. In adaptive immune responses, the P2X7 receptor has been linked to T cell activation, differentiation, and apoptosis induc...
P2Y11 receptor expression by human lymphocytes: evidence for two cAMP-linked purinoceptors
European Journal of Pharmacology, 2001
The effects of extracellular ATP, ADP, AMP and adenosine on cAMP accumulation have been studied in freshly isolated B-lymphocytes from patients with chronic lymphocytic leukemia. Extracellular ATP and several nucleotide analogs stimulated cAMP Ž. accumulation with the following order of potency: ATP EC s 120 " 20 mM) ADP 4 AMP. ADP was less effective than ATP and 50 may be a partial agonist. AMP exhibited variable but generally weak activity. The stable analog of ATP, a ,b-methylene ATP Ž. EC s 110 " 15 mM also stimulated cAMP accumulation and exhibited similar efficacy to ATP. The P2Y receptor agonist, UTP had 50 2 X 11 2A Coordinate activation of P2Y and A receptors may influence the developmental fate of normal B-lymphocytes. q 2001 Published by 11 2A Elsevier Science B.V.
The Journal of Immunology, 2009
Extracellular NAD induces the ATP-independent activation of the ionotropic P2X7 purinergic receptor (P2X7R) in murine T lymphocytes via a novel covalent pathway involving ADP-ribosylation of arginine residues on the P2X7R ectodomain. This modification is catalyzed by ART2.2, a GPI-anchored ADP-ribosyltransferase (ART) that is constitutively expressed in murine T cells. We previously reported that ART2.1, a related ecto-ART, is up-regulated in inflammatory murine macrophages that constitutively express P2X7R. Thus, we tested the hypothesis that extracellular NAD acts via ART2.1 to regulate P2X7R function in murine macrophages. Coexpression of the cloned murine P2X7R with ART2.1 or ART2.2 in HEK293 cells verified that P2X7R is an equivalent substrate for ADP-ribosylation by either ART2.1 or ART2.2. However, in contrast with T cells, the stimulation of macrophages or HEK293 cells with NAD alone did not activate the P2X7R. Rather, NAD potentiated ATP-dependent P2X7R activation as indica...
Autocrine regulation of T-cell activation by ATP release and P2X7 receptors
The FASEB Journal, 2009
T-cell activation requires the influx of extracellular calcium, although mechanistic details regarding such activation are not fully defined. Here, we show that P2X 7 receptors play a key role in calcium influx and downstream signaling events associated with the activation of T cells. By real-time PCR and immunohistochemistry, we find that Jurkat T cells and human CD4 ؉ T cells express abundant P2X 7 receptors. We show, using a novel fluorescent microscopy technique, that T-cell receptor (TCR) stimulation triggers the rapid release of ATP (<100 M). This release of ATP is required for TCR-mediated calcium influx, NFAT activation, and interleukin-2 (IL-2) production. TCR activation up-regulates P2X 7 receptor gene expression. Removal of extracellular ATP by apyrase or alkaline phosphatase treatment, inhibition of ATP release with the maxi-anion channel blocker gadolinium chloride, or siRNA silencing of P2X 7 receptors blocks calcium entry and inhibits T-cell activation. Moreover, lymphocyte activation is impaired in C57BL/6 mice that express poorly functional P2X 7 receptors, compared to control BALB/c mice, which express fully functional P2X 7 receptors. We conclude that ATP release and autocrine, positive feedback through P2X 7 receptors is required for the effective activation of T cells.-Yip, L., Woehrle, T., Corriden, R., Hirsh, M., Chen, Y., Inoue, Y., Ferrari, V., Insel, P. A., Junger, W. G. Autocrine regulation of T-cell activation by ATP release and P2X 7 receptors. FASEB J. 23, 1685-1693 (2009)
Dual Effect of Nucleotides on P2Y Receptors
IUBMB Life, 2000
The interaction of ADP, 2MeSADP, and ADPb S with the adenine nucleotide receptor P2Y 1 in the hP2Y 1 -1321N1 cell line and of UDP with a receptor or receptors recognizing pyrimidine nucleotides in NG108-15 cells was studied over a wide range of ligand concentrations. Bell-shaped doseresponse curves for stimulation of phosphoinositide hydrolysis were obtained in these cells. This dual behavior of the agonists studied was characterized by two dissociation constants, K agon and K antag , which quantify the agonistic and antagonistic activity of these ligands and can be compared with the conventional EC 50 and IC 50 values, respectively. The data revealed a common pattern of agonistic and antagonistic behavior of nucleoside diphosphates and their derivatives at these two types of P2Y receptors, pointing to some similar properties of their nucleotide binding sites. IUBMB Life, 50: 99 -103, 2000