Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NK cell proliferation is suppressed in some patients with cancer by unknown mechanisms. Because purine metabolites released into the extracellular space during cell lysis may affect cell function, we hypothesized that these metabolites could serve as feedback regulators of NK cell proliferation. Sorted NK (CD56+/CD3-) cells were incubated with IL-2 (1000 U/ml) in a 4-day thymidine uptake assay with or without 10-10,000 microM of nucleotides. Adenine nucleotides inhibited NK cell proliferation, with ATP = ADP > 5'-adenylylimidodiphosphate > AMP = adenosine; ADP-ribose and nicotinamide adenine dinucleotide, but not nicotinamide or UTP, caused a dose-dependent suppression of thymidine uptake. A total of 100 microM ATP, a concentration that induced a maximal (80%) inhibition of thymidine uptake, did not inhibit cytotoxic activity against K562 targets. Because NK cells retained the ability to lyse K562 targets 4 days after exposure to 500 microM ATP or 1000 microM adenosine, inhibition of thymidine uptake was not due to cell death. Incubation of NK cells with dibutyryl cAMP and forskolin also suppressed thymidine uptake. Cholera toxin and pertussis toxin suppressed NK cell proliferation. Pertussis toxin did not block the adenine nucleotide effects. Further, ATP, but not adenosine or other nucleotides, markedly increased intracellular cAMP in a dose-dependent manner. The ATP-induced increase in cAMP was specific to cytolytic cells, because CD19+ B cells and CD4+ T cells did not increase their intracellular cAMP. These studies demonstrate that NK proliferation is regulated through purine receptors by adenine nucleotides, which may play a role in decreased NK cell activity. The response to adenine nucleotides is lineage-specific.
 ...
PMID:Purine metabolites suppress proliferation of human NK cells through a lineage-specific purine receptor. 1035 89

1. Northern blotting experiments have been performed with RNA extracted from several cell lines derived from the human lung in order to detect P2Y1, P2Y2, P2Y4 and P2Y6 mRNA. We have investigated the 1HAEo- and 16HBE14o- epithelial cell lines derived from the airway epithelium, the A549 cell line displaying properties of type II alveolar epithelial cells, the CALU-3 serous cells, the 6CFSMEo- submucosal cells and the HASMSC1 airway smooth muscle cells. We have also evaluated one pancreatic epithelial cell line called CFPAC-1. These experiments revealed that P2Y2 and P2Y6 mRNA are co-expressed in the IHAEo-, 16HBE14o- and A549 epithelial cell lines. The CFPAC-1 pancreatic cell line was strongly positive for the P2Y2 receptor. No signal was obtained for the P2Y1 and P2Y4 receptors. 2. We have then performed RT-PCR experiments with specific oligonucleotides of these last two P2Y receptors with the RNA used for the Northern blotting experiments. P2Y4 mRNA was detected in five cell lines: 1HAEo-, 16HBE14o-, 6CFSMEo-, HASMSC1 and CFPAC-1. P2Y1 mRNA was only detected in the CALU-3 cell line. 3. Inositol trisphosphates assays have identified a response typical of the P2Y2 receptor in the 1HAEo- and the 16HBE14o- airway epithelial cell lines which co-express P2Y2 and P2Y6 mRNA. By contrast, the 6CFSMEo- submucosal cells expressed a UTP-specific response which displayed pharmacological characteristics compatible with the human P2Y4 receptor: in particular, there was no response to UDP or ATP and the UTP effect was totally inhibited by pertussis toxin.
 ...
PMID:Expression of P2Y receptors in cell lines derived from the human lung. 1038 59

Rat mucosal mast cells express P2 purinoceptors, occupation of which mobilizes cytosolic Ca2+ and activates a potassium conductance. The primary function of this P2 system in mast cell biology remains unknown. Here, we show that extracellular ADP causes morphological changes in rat bone marrow-cultured mast cells (BMMC) typical of those occurring in cells stimulated by chemotaxins, and that the nucleotides ADP, ATP, and UTP are effective chemoattractants for rat BMMC. ADP was also a chemotaxin for murine J774 monocytes. The nucleotide selectivity and pertussis toxin sensitivity of the rat BMMC migratory response suggest the involvement of P2U receptors. Poorly hydrolyzable derivatives of ADP and ATP were effective chemotaxins, obviating a role for adenosine receptors. Buffering of external Ca2+ at 100 nM or reduction of the electrical gradient driving Ca2+ entry (by elevating external K+) blocked ADP-driven chemotaxis, suggesting a role for Ca2+ influx in this process. Anaphylatoxin C5a was a potent chemotaxin (EC50 approximately 0.5 nM) for J774 monocytes, but it was inactive on rat BMMC in the presence or absence of laminin. Ca2+ removal or elevated [K+] had modest effects on C5a-driven chemotaxis of J774 cells, implicating markedly different requirements for Ca2+ signaling in C5a- vs ADP-mediated chemotaxis. This is supported by the observation that depletion of Ca2+ stores with thapsigargin completely blocked migration induced by ADP but not C5a. These findings suggest that adenine nucleotides liberated from parasite-infested tissue could participate in the recruitment of mast cells by intestinal mucosa.
 ...
PMID:Chemotaxis of rat mast cells toward adenine nucleotides. 1039 94

1. In the process of cloning the human P2Y2 receptor in order to establish 1321N1 cell lines expressing this receptor, we detected a gene polymorphism characterized by an arginine 334 to cysteine 334 transition. 2. The frequency distribution of the polymorphism was studied in a European population. We observed that 66% of the tested persons are homozygotes R/R, 29% are heterozygotes R/C and 5% are homozygotes C/C. The frequency of the R allele was 0.8 versus 0.2 for the C allele. 3. We stably expressed each form of the human P2Y2 receptor into 1321N1 cells and isolated clones by limiting dilution. The effects of nucleotides and antagonists on inositol trisphosphate accumulation and cyclic AMP formation were compared between the two cell lines. 4. The time-courses of inositol trisphosphate accumulation as well as concentration-response curves characterizing the effects of UTP, ATP, AP4A and ATP gamma S were mostly similar, except for slight kinetic differences (slower time-course with the 334C form). 5. The sensitivity to pertussis toxin of inositol trisphosphates accumulation was critically dependent on the agonist concentration and stimulation duration, suggesting the involvement of a Gi.0 protein during the early stimulation by low nucleotide concentrations. No inhibition of cyclic AMP accumulation could be detected. These properties were observed with both polymorphic receptors.
 ...
PMID:Human P2Y2 receptor polymorphism: identification and pharmacological characterization of two allelic variants. 1040 62

Mouse L-fibroblast cells stably transfected with either type 1 Ins(1, 4,5)P(3) receptor (InsP(3)R) cDNA (L15) or the vector control (Lvec) have been used to investigate the functional consequences of increased InsP(3)R density on receptor-mediated Ca(2+) signalling. L15 cells express approx. 8-fold higher levels of the type 1 InsP(3)R compared with Lvec cells, which endogenously express essentially only the type 1 InsP(3)R protein. Stimulation of Lvec and L15 cells with UTP or ATP increased cytosolic Ca(2+) concentration to a greater extent in L15 cells at all agonist concentrations. UTP and ATP were equipotent, suggestive of the presence of endogenous cell-surface metabotropic P2Y(2)-purinoceptors. In both cell clones the purinoceptors were coupled via pertussis-toxin-insensitive G-protein(s) to phospholipase C activation, resulting in similar concentration-dependent accumulations of InsP(3). Single-cell microfluorimetry revealed that overexpression of InsP(3)Rs reduced the threshold for purinoceptor-mediated Ca(2+) signalling. L-fibroblasts also exhibited temporally complex sinusoidal cytosolic Ca(2+) oscillations in response to submaximal agonist concentrations, with significant increases in oscillatory frequencies exhibited by cells overexpressing InsP(3)Rs. Sustainable oscillatory responses were dependent on Ca(2+) entry and, at higher agonist concentrations, cytosolic Ca(2+) oscillations were superseded by biphasic peak-and-plateau Ca(2+) responses. Overexpression of InsP(3)Rs in L15 cells resulted in a 4-fold reduction in the threshold for this change in the temporal pattern of Ca(2+) mobilization. These data provide the first direct evidence demonstrating that altering the expression of the type 1 InsP(3)R significantly affects receptor-mediated InsP(3)-induced Ca(2+) mobilization.
 ...
PMID:Enhanced purinoceptor-mediated Ca2+ signalling in L-fibroblasts overexpressing type 1 inositol 1,4,5-trisphosphate receptors. 1041 48

While it is recognized that activated dendritic cells perform their immune functions with greater efficacy, it is not altogether clear what factors are responsible for such activation. Recent evidence points to an important role for extracellular nucleotides in the modulation of leukocyte function. In the present study we investigated the ability of extracellular nucleotides to activate CD11c(+) murine dendritic cells. Mobilization of intracellular calcium was observed following treatment of these cells with UTP or UDP, but not ATP. Furthermore, this nucleotide receptor was pertussis toxin-sensitive, suggesting the presence of a P2Y nucleotide receptor. Such receptors were not present on murine peritoneal macrophages or on CD11c-negative leukocyte populations. Importantly, activation of these P2Y nucleotide receptors on dendritic cells provided a potent stimulus for cytokine mRNA expression and secretion. Thus, expression of a P2Y nucleotide receptor on CD11c(+) dendritic cells functions to mobilize intracellular calcium and to induce cytokine production.
 ...
PMID:Extracellular uridine nucleotides initiate cytokine production by murine dendritic cells. 1044 14

1. Our aim was to assess whether ATP-induced inward currents in microglia are due to a single or more than one purinergic receptor. The ATP dose-response curve showed two components, whose presence might be due to the activation of high and low affinity receptors. 2. The P2Z/P2X7 specific receptor agonist benzoylbenzoyl-ATP (Bz-ATP) and some P2 receptor agonists were tested. The rank order of potency was Bz-ATP >> ATP = 2-methylthio-ATP (2-MeSATP) > alpha, beta-methylene ATP (alpha,beta-meATP) >= ADP. beta, gamma-MethyleneATP (beta,gamma-meATP), UTP and adenosine were ineffective. 3. The non-specific P2 receptor antagonist suramin antagonized by 92 +/- 2 % the inward current induced by 100 microM ATP, and by 51 +/- 8 and 68 +/- 6 % those induced by 3 mM ATP and 100 microM Bz-ATP, respectively. The P2Z/P2X7 antagonist oxidized ATP (oATP) almost abolished the inward current induced by 3 mM ATP or Bz-ATP, but was ineffective against 100 microM ATP. 4. Inward currents induced by low ATP concentrations (<= 100 microM) were generally followed by an almost complete and irreversible desensitization, while those elicited by ATP >= 1 mM showed only a partial decline. Interestingly, the inward current induced by 100 microM 2-MeSATP showed a large desensitization, while that induced by Bz-ATP did not. 5. In voltage-ramp experiments, the 100 microM ATP-induced current exhibited a slight inward rectification more visible at negative potentials, while the 3 mM ATP-induced current did not. 6. ATP induced a fast and large increase in [Ca2+] that promptly recovered in the continuous presence of low ATP doses, but did not recover in high ATP doses. As with desensitization, the response to Bz-ATP mimicked that of high doses of ATP. 7. When Ca2+ mobilization due to P2Y receptors was blocked by thapsigargin-induced Ca2+ depletion or by pertussis toxin treatment, 10 microM ATP was still able to induce a Ca2+ transient, which represented the contribution of the Ca2+ influx induced by P2X receptors 8. In conclusion, the inward currents and a fraction of the Ca2+ transients induced by ATP in microglia are due to at least two ATP-sensitive receptor channel types, whose different properties and sensitivity to ATP may be associated with different functional roles.
 ...
PMID:Two different ionotropic receptors are activated by ATP in rat microglia. 1045 86

Uridine triphosphate (UTP) evoked inhibition of adrenaline-evoked cAMP accumulation in cultured equine epithelial cells (EC50, 1.8 +/- 0.2 microM) and this effect was mimicked by 5-Br-UTP (EC50, 6.6 +/- 1.8 microM) and uridine diphosphate (UDP; EC50, 96 +/- 26 microM). This inhibitory action of UTP was abolished by pre-treating cells with pertussis toxin (10 ng ml-1, 24 h). UTP (EC50, 2.3 +/- 0.3 microM) and 5-Br-UTP (EC50, 29.4 +/- 9.4 microM) also increased intracellular free calcium ([Ca2+]i) whilst UDP did not; the two effects are thus differentially sensitive to these pyrimidine nucleotides. ATP evoked cAMP accumulation in control cells and this response was unaffected by pertussis toxin. There is, therefore, no indication that ATP activates the pertussis toxin-sensitive inhibitory pathway. The UTP-evoked inhibition of cAMP accumulation was abolished by isobutylmethylxanthine (IBMX, 5 mM) and so the negative control over cAMP levels appears to be mediated by receptors that are selectively activated by pyrimidine nucleotides and permit control over phosphodiesterase activity.
 ...
PMID:Pyrimidine nucleotide-evoked inhibition of cyclic AMP accumulation in equine epithelial cells. 1048 Dec 22

The mechanisms by which extracellular nucleotides (ATP and UTP) regulate intracellular Ca2+ in cultured pig tracheal gland cells were studied. The calcium response induced by ATP or UTP was composed of a peak response and a steady plateau. In the absence of extracellular Ca2+, the peak response of the cells to both ATP and UTP was smaller, and no subsequent plateau was observed. After treatment of the cells with pertussis toxin, the peak response to UTP was significantly smaller and no plateau was seen even in the presence of extracellular Ca2+, but pertussis toxin did not change the effect of ATP. Pretreatment with U107, a phospholipase C inhibitor, almost abolished the calcium response to both ATP and UTP. Immunocytochemistry showed that in these cells, the IP3 receptor was localized in the cytoplasm (including the endoplasmic reticulum) of the cells. Our results indicate that both release of calcium from the intracellular store and Ca2+ influx across the cell membrane contribute to the mobilization of [Ca2+]i upon stimulation with nucleotides, that ATP and UTP regulate intracellular Ca2+ predominantly via the G protein-phospholipase C-IP3 pathway, and that ATP and UTP may act via distinct subtypes of P2Y receptors.
 ...
PMID:Regulation of intracellular calcium by extracellular nucleotides in pig tracheal submucosal gland cells. 1064 67

We recently cloned and expressed a novel P2Y receptor (tp2y receptor) from a turkey cDNA library. Expression of this receptor in 1321N1 human astrocytoma cells confers nucleotide-dependent stimulation of phospholipase C activity; however, as we demonstrate here, it also confers nucleotide-dependent inhibition of adenylyl cyclase. Both the phospholipase C and adenylyl cyclase responses were promoted by receptor agonists over a similar range of concentrations. Moreover, not only did UTP and ATP activate the avian receptor but ITP, GTP, xanthosine 5'-triphosphate, and CTP were also agonists, with EC(50) values ranging between 0.1 and 1 microM. Similar potencies, rank-order, and selectivity of nucleotide agonists were also demonstrated for intracellular Ca(2+) mobilization measured during a 30-s stimulation under constant superfusion conditions. This observation indicates that receptor activation by nucleoside 5'-triphosphates is not produced by interconversion of these nucleotides into ATP or UTP. Pretreatment of cells with pertussis toxin completely abolished the inhibitory effect of nucleotide agonists on adenylyl cyclase, whereas the activation of phospholipase C was only partially inhibited. These results demonstrate that the avian P2Y receptor is a nucleoside triphosphate receptor of broad agonist selectivity that interacts with both pertussis toxin-insensitive and -sensitive G proteins to activate phospholipase C and to inhibit adenylyl cyclase. This is the first cloned P2Y receptor that is clearly Gi/adenylyl cyclase-linked.
 ...
PMID:A molecularly identified P2Y receptor simultaneously activates phospholipase C and inhibits adenylyl cyclase and is nonselectively activated by all nucleoside triphosphates. 1072 29


<< Previous 1 2 3 4 5 6 7 8 9 10