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)

1. As well as the presence of P2Z purinoceptors previously found in macrophages, we identified pyrimidinoceptors in RAW 264.7 cells, which activate phospholipase C (PLC) and phospholipase A2 (PLA2). 2. The relative potency of agonists to stimulate inositol phosphate (IP) formation and arachidonic acid (AA) release was UTP = UDP > > ATP, ATP gamma S, 2MeSATP. For both signalling pathways, the EC50 values for UTP and UDP (3 microM) were significantly lower than that for ATP and all other analogues tested (> 100 microM). 3. UTP and UDP displayed no additivity in terms of IP formation and AA release at maximally effective concentrations. 4. UTP-, but not ATP-, evoked AA release was 60% inhibited by pertussis toxin (PTX), while stimulation of IP formation by both agonists was unaffected. Short-term treatment with phorbol 12-myristate 13-acetate (PMA) led to a dose-dependent inhibition of IP responses to UTP and UDP, but failed to affect the AA responses. Removal of extracellular Ca2+ inhibited the PI response to UTP, but abolished its AA response. 5. ATP-induction of these two transmembrane signal pathways was decreased in high Mg(2+)-containing medium but potentiated by the removal of extracellular Mg2+. 6. Suramin and reactive blue displayed equal potency to inhibit the IP responses of UTP and ATP. 7. Both UTP and UDP (0.1-100 microM) induced a sustained increase in [Ca2+]i which lasted for more than 10 min. 8. Taken together, these results indicate that in mouse RAW 264.7 macrophages, pyrimidinoceptors with specificity for UTP and UDP mediate the activation of PLC and cytosolic (c) PLA2. The activation of PLC is via a PTX-insensitive G protein, whereas that of cPLA2 is via a PTX-sensitive G protein-dependent pathway. The sustained Ca2+ influx caused by UTP contributes to the activation of cPLA2. RAW 264.7 cells also possess P2z purinoceptors which mediate ATP(4-)-induced PLC and PLA2 activation.
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PMID:Pyrimidinoceptor-mediated activation of phospholipase C and phospholipase A2 in RAW 264.7 macrophages. 888 7

The P2Y4 receptor is a new member of the P2Y family which functionally behaves as a pyrimidinergic receptor. The pharmacological properties of the human P2Y4 receptor have been characterized following its stable expression in 1321N1 astrocytoma cells. UTP induced a biphasic accumulation of inositol trisphosphates, with an early peak at 30 s followed by a smaller but more sustained accumulation. ATP was a pure antagonist at early times and later behaved as a partial agonist. At 20 min, the rank order of potency of various nucleotides was the following: UTP > UDP = deoxy UTP > 5-bromo-UTP > ITP > ATP. Diadenosine polyphosphates also stimulated the production of inositol trisphosphates (after 20 min), more potently than ATP, but their maximal effect represented only 20-25% of that of UTP. Pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid inhibited strongly the UTP response, whereas suramin was inactive and reactive blue 2 had an intermediate effect. Pertussis toxin inhibited the response to UTP at early times (62 +/- 5% inhibition at 30 s), but its effect was no longer observed at 5 or 20 min. It is speculated that the P2Y4 receptor can exist in two distinct activation states differing in terms of time-course, specificity for uridine nucleotides and G-protein coupling.
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PMID:Pharmacological characterization of the human P2Y4 receptor. 899 25

1. Extracellular adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) have been shown to activate a nucleotide receptor (P2U receptor) in rat mesangial cells that mediates phosphoinositide and phosphatidylcholine hydrolysis by phospholipases C and D, respectively. This is followed by an increased activity of the mitogen-activated protein kinase cascade and cell proliferation. Here we show that ATP and UTP potently stimulate the stress-activated protein kinase pathway and phosphorylation of the transcription factor c-Jun. 2. Both nucleotides stimulated a rapid (within 5 min) and concentration-dependent activation of stress-activated protein kinases as measured by the phosphorylation of c-Jun in a solid phase kinase assay. 3. When added at 100 microM the rank order of potency of a series of nucleotide analogues for stimulation of c-Jun phosphorylation was UTP > ATP = UDP = ATP gamma S > 2-methylthio-ATP > beta gamma-imido-ATP = ADP > AMP = UMP = adenosine = uridine. Activation of stress-activated protein kinase activity by ATP and UTP was dose-dependently attenuated by suramin. 4. Down-regulation of protein kinase C-alpha, -delta and -epsilon isoenzymes by 24 h treatment of the cells with 12-O-tetradecanoylphorbol 13-acetate did not inhibit ATP- and UTP-induced activation of c-Jun phosphorylation. Furthermore, the specific protein kinase C inhibitors, CGP 41251 and Ro 31-8220, did not inhibit nucleotide-stimulated c-Jun phosphorylation, suggesting that protein kinase C is not involved in ATP- and UTP-triggered stress-activated protein kinase activation. 5. Pretreatment of the cells with pertussis toxin or the tyrosine kinase inhibitor, genistein, strongly attenuated ATP- and UTP-induced c-Jun phosphorylation. Furthermore, N-acetyl-cysteine completely blocked the activation of stress-activated protein kinase in response to extracellular nucleotide stimulation. 6. In summary, these results suggest that ATP and UTP trigger the activation of the stress-activated protein kinase module in mesangial cells by a pathway independent of protein kinase C but requiring a pertussis toxin-sensitive G-protein and tyrosine kinase activation.
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PMID:Stimulation by extracellular ATP and UTP of the stress-activated protein kinase cascade in rat renal mesangial cells. 913 85

1. The short circuit current (ISC) technique was used to quantify electrolyte transport by equine cultured sweat gland epithelia. Adenosine 5'-triphosphate (ATP) and certain related compounds, caused transient increases in ISC when added to the apical solution. The order of potency was uridine triphosphate (UTP) > ATP > ADP > > AMP = adenosine. 2. The responses to apical nucleotides were due to chloride and bicarbonate secretion and were reduced in pertussis toxin-treated cells. P2-receptors sensitive to uridine 5'-triphosphate (UTP), that interact with inhibitory G proteins, therefore appear to be present in the apical membrane. 3. Responses to ATP and UTP were reduced in cells loaded with BAPTA, a calcium chelator. BAPTA attenuated the response to ATP more than the response to UTP suggesting that these nucleotides may not act via a common pathway. 4. Cross-desensitization experiments indicated that two populations of UTP-sensitive receptor were present. One was sensitive to UTP and ATP, whereas the second was sensitive only to UTP. Uridine diphosphate appeared to activate the ATP-insensitive receptor population selectively. 5. These data suggest that apical pyrimidinoceptors may be expressed by these cells. The physiological role of these receptors is unknown but they may allow the autocrine regulation of epithelial function.
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PMID:Purine and pyrimidine nucleotide receptors in the apical membranes of equine cultured epithelia. 914 99

The P2Y6 receptor is a recently cloned P2 receptor which displays a high sensitivity for diphosphonucleotides. In 1321N1 astrocytoma cells stably expressing this receptor, UDP induced a slow and sustained accumulation of inositol trisphosphate via a pertussis toxin-insensitive G-protein: the maximal level was only reached after 15 min and a significant response was maintained for at least 3 h. A full second response to UDP was obtained after the first 45-min stimulation, but was lost after 165 min. This slow and sustained time-course and the lack of desensitization was reproduced with ADP. UTP was unable to restimulate the P2Y4 receptor, another recently cloned P2 receptor with a preference for UTP, after the first 5-min stimulation. The P2Y4 receptor is thus rapidly desensitized whereas desensitization of the P2Y6 receptor is delayed. The rank order of potency of various diphosphonucleotides at the P2Y6 receptor was: UDP > TDP > IDP > GDP > ADP >> CDP. The activity of three non-specific antagonists of P2 receptors was characterized by the following rank order of potency: reactive blue 2 > pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) > suramin. In conclusion, the most impressive features of the human P2Y6 receptor revealed by this study are the slow and sustained time-course of its activation and its high resistance to desensitization.
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PMID:Slow desensitization of the human P2Y6 receptor. 922 17

1. We have investigated the effects of nucleotide analogues on cyclic AMP formation in mouse J774 macrophages and the mechanisms involved. 2. UTP, in the concentration range 0.1-100 microM, induced concentration-dependent potentiation of prostaglandin E1 (PGE1)-induced cyclic AMP formation, but had no effect on basal cyclic AMP formation. UDP showed an equal potency, while 2-methylthio ATP, alpha, beta-methylene ATP and beta,gamma-methylene ATP gave either a slight increase or had no effect at concentrations up to 100 microM. ATP, although 100 fold less effective than UTP, also caused cyclic AMP potentiation, but had no effect on agonist-stimulated or basal cyclic AMP levels. 3. The cyclic AMP potentiation effect of UTP correlated with increased [Ca2+]i and inositol phosphate (IP) formation over the same concentration range. 4. Ionomycin, which evokes an increase in [Ca2+]i without affecting IP formation, did not cause an increase in cyclic AMP content, indicating that UTP-induced cyclic AMP regulation is not due to activation of Ca(2+)-sensitive adenylyl cyclase isoforms. 5. Although reduced, UTP potentiation was seen in cells incubated in a Ca(2+)-free and/or BAPTA-containing medium. Under these conditions, the UTP-increased IP accumulation was similarly reduced. 6. Exposure of cells to phorbol 12-myristate 13-acetate (PMA) also increased PGE1 stimulation of cyclic AMP levels, and the UTP-induced potentiation of cyclic AMP formation was inhibited by either staurosporine or Ro 31-8220. Pretreatment of cells with PMA for 4-24 h resulted in marked attenuation of UTP-stimulated cyclic AMP potentiation. 7. Pretreatment with pertussis toxin (24 h, 100 ng ml-1) did not significantly affect UTP-induced cyclic AMP potentiation and IP formation, although it increased the cyclic AMP response to PGE1. 8. Analysis of J774 cells by Western blotting with antibodies specific for different protein kinase C (PKC) isoforms shows the presence of the beta I, beta II, delta, epsilon, eta, mu, lambda and zeta isoforms. Moreover, UTP significantly increased the level of PKC beta I, beta II, delta, epsilon, mu, lambda and zeta immunoreactivity in the membrane fraction and decreased the cytosolic reactivity of PKC beta II, delta, epsilon and zeta. 9. Immunoblot studies also indicate the presence of type II adenylyl cyclase. 10. These results indicate that PKC is required for the potentiation of adenylyl cyclase activity by macrophage pyrimidinoceptors, which exhibit a higher specificity for UTP and UDP than for ATP.
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PMID:Involvement of protein kinase C in the UTP-mediated potentiation of cyclic AMP accumulation in mouse J774 macrophages. 928 13

Incubation of Neuro 2A mouse neuroblastoma cells with UTP and UDP results in a concentration-dependent increase in the accumulation of inositol phosphates with equal potency and maximal effect; ATP, ADP, and 2-methylthioadenosine 5'-triphosphate were much less potent, indicating the expression of P2Y receptor in these cells. The effects of UTP and ATP were not affected by pretreatment of cells with pertussis toxin, indicating that the P2Y receptor in Neuro 2A cells is coupled to pertussis toxin-insensitive Gq protein. Short-term (10 min) treatment of cells with 1 microM 12-O-tetradecanoylphorbol 13-acetate (TPA) resulted in the inhibition of the UTP and ATP effects; this inhibitory effect was gradually attenuated with increased length of TPA treatment (1.5-6 h) and was not seen after long-term (24 h) treatment. Western blot analysis showed the expression of protein kinase C (PKC) alpha, epsilon, theta, and zeta in Neuro 2A cells. Translocation of PKC alpha, epsilon, and theta from the cytosol to the membrane was seen after 10 min or 1.5 h of treatment with TPA. However, partial and complete down-regulation of both membrane PKC alpha and theta were seen after 3 and 6 h of treatment, respectively. In contrast, the TPA-induced translocation of PKC epsilon was maintained after 3-6 h of treatment, and almost complete down-regulation occurred only after a 24-h treatment. The observed TPA-induced inhibition of UTP- or ATP-stimulated phosphoinositide hydrolysis, therefore, correlated well with the extent of translocation of PKC epsilon. Phosphoinositide hydrolysis induced by AlF4-, but not Ca2+ ionophores, was inhibited by a 10-min treatment with TPA. This was not seen after a 24-h treatment, indicating that the site of action of PKC epsilon in the P2Y receptor/Gq protein/phospholipase C beta pathway might be the Gq protein. This is the first study to show the existence of the P2Y receptor in Neuro 2A cells and the possible involvement of neuronal PKC epsilon in the regulation of the receptor-mediated phosphoinositide turnover.
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PMID:P2Y receptor linked to phospholipase C: stimulation of neuro 2A cells by UTP and ATP and possible regulation by protein kinase C subtype epsilon. 932 69

Signal transduction via P2 purinergic receptors was investigated in HSG cells, a continuous cell line originally derived from an irradiated human salivary gland. Ligand specificity for nucleotide receptors in HSG cells was investigated with various nucleotides and their analogues. Inositol 1,4,5-trisphosphate (IP3) production was significantly increased by ATP, UTP and ATP gamma S. The ligand specificity of this effect agreed well with that of the P2U purinergic receptor. On the other hand, 45Ca2+ influx was stimulated by ATP, UTP > ATP gamma S, ADP, UDP > ADP beta S > AMPPNP, GTP, TTP > CTP, GDP, TDP, AMPPCP, AMPCPP. This ligand specificity of 45Ca2+ influx was much broader than IP3 production. Also pertussis and cholera toxin had no effect on both IP3 production and 45Ca2+ influx by ATP or UTP. 3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (Bz-ATP) stimulates 45Ca2+ influx more effectively than IP3 formation. A 53-kDa membrane protein was photolabelled with [alpha-32P]Bz-ATP. This 53-kDa protein is a putative P2 purinergic receptor. In particular, the labelling was inhibited by a ligand profile that corresponded to that for 45Ca2+ influx. These findings suggest that nucleotides stimulate 45Ca2+ influx and IP3 formation by separate pathways via pertussis and cholera toxin-insensitive G proteins. Thus, in HSG cells, IP3 formation is coupled to the P2U subclass, while 45Ca2+ influx is coupled to another subclass, such as P2X, that regulates calcium channels.
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PMID:A calcium channel in human submandibular duct cell line, HSG cells, not regulated by P2U purinergic receptor-mediated intracellular calcium mobilization. 934 17

The P2Y2 receptor is a uridine/adenosine triphosphate (UTP/ATP)-sensitive G-protein-linked nucleotide receptor that previously has been reported to stimulate the phosphoinositide signaling pathway. Messenger RNA for this receptor has been detected in brain tissue. We have investigated the coupling of the molecularly defined rat P2Y2 receptor to neuronal N-type Ca2+ channels and to M-type K+ channels by heterologous expression in rat superior cervical sympathetic (SCG) neurons. After the injection of P2Y2 cRNA, UTP inhibited the currents carried by both types of ion channel. As previously reported [Filippov AK, Webb TE, Barnard EA, Brown DA (1997) Inhibition by heterologously expressed P2Y2 nuerones. Br J Pharmacol 121:849-851], UTP inhibited the Ca2+ current (ICa(N)) by up to 64%, with an IC50 of approximately 0.5 microM. We now find that UTP also inhibited the K+M current (IK(M)) by up to 61%, with an IC50 of approximately 1.5 microM. UTP had no effect on either current in neurons not injected with P2Y2 cRNA. Structure-activity relations for the inhibition of ICa(N) and IK(M) in P2Y2 cRNA-injected neurons were similar, with UTP >/= ATP > ITP >> GTP,UDP. However, coupling to these two channels involved different G-proteins: pretreatment with Pertussis toxin (PTX) did not affect UTP-induced inhibition of IK(M) but reduced inhibition of ICa(N) by approximately 60% and abolished the voltage-dependent component of this inhibition. In unclamped neurons, UTP greatly facilitated depolarization-induced action potential discharges. Thus, the single P2Y2 receptor can couple to at least two G-proteins to inhibit both Ca2+N and K+M channels with near-equal facility. This implies that the P2Y2 receptor may induce a broad range of effector responses in the nervous system.
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PMID:P2Y2 nucleotide receptors expressed heterologously in sympathetic neurons inhibit both N-type Ca2+ and M-type K+ currents. 965 Dec

The contractile effect of ATP given alone or in the presence of other nucleotides was studied in rat aortic strips. A sustained contraction in response to ATP (30 microM to 10 mM) was observed during UTP exposure instead of the fast transient contraction produced via P2x purinoceptor activation in the absence of UTP, and contrary to the relaxation elicited when the tone had been raised by noradrenaline and KCl. This sustained ATP effect was produced in the smooth muscle and not via the same mechanism through which UTP elicited contraction, since the contractions in response to UTP and ATP were additive. They were also coupled to different transduction pathways: the effect of UTP but not that of ATP was pertussis toxin-sensitive. In contrast to the fast transient ATP contraction during basal tone, the sustained response was not desensitized by alpha,beta-methylene ATP exposure (30 microM), but was inhibited by reactive blue 2 (10 and 30 microM). Among the nucleotides assayed, UDP and ATPgammaS also enabled ATP to elicit a sustained contraction. ADP, AMP, dATP, 2-methylthio ATP, alpha,beta-methylene ATP, GTP, GDP, GMP, CTP and ITP also induced a sustained contraction in the presence of UTP. However, adenosine (1 mM) and adenine (0.3 to 3 mM) induced relaxation when the tone had been raised by UTP. According to these results a non-selective nucleotide receptor, different from the P2 purinoceptors functionally characterized so far, seems to mediate sustained contractions in rat aortic strips in the presence of UTP, UDP or ATPgammaS.
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PMID:Pharmacological evidence for a receptor mediating sustained nucleotide-evoked contractions of rat aorta in the presence of UTP. 967 Nov 2


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