Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Uterine artery endothelial cells (UAEC) derived from pregnant (P-UAEC) and nonpregnant (NP-UAEC) ewes retain pregnancy-specific differences in cell signaling as well as vasodilator production through passage 4. In particular, when P- and NP-UAEC are stimulated with ATP over a 2.5 min recording period, they exhibit similar initial transient peaks in the intracellular free Ca(2+) concentration ([Ca(2+)](i)), but the P-UAEC show a heightened sustained phase. In order to establish whether this was due to an altered subclass of purinergic receptor (P2), both the dose dependency of [Ca(2+)](i) responses to ADP and UTP and the profile of purinergic receptor expression are determined in NP- and P-UAEC. Our findings indicate that while several isoforms of P2X and P2Y receptors are present, it is P2Y2 that is responsible for the ATP-induced initial transient peak in both cell types. We also characterized several key components of the ATP-induced Ca(2+) signaling cascade, including the inositol 1,4,5-trisphosphate receptor and G-proteins, but could not confirm any pregnancy-specific variation in the protein expression that correlated with pregnancy-specific differences in prolonged Ca(2+) signaling. We thus investigated whether such a difference may be inherent to the cell itself rather than specific to the purinergic receptor-signaling pathway. Using thapsigargin (Tg), we were able to demonstrate that the initial Tg-sensitive intracellular pool of Ca(2+)is nearly identical with the capacity in both cell types, but the P-UAEC is nonetheless capable of greater capacitative Ca(2+) entry (CCE) than NP-UAEC. Furthermore, CCE induced by Tg could be dramatically inhibited by 2-aminoethoxydiphenyl borate, suggesting a role for store-operated channels in the ATP-induced [Ca(2+)](i) response. We conclude that changes at the level of capacitative entry mechanisms rather than switching of receptor subtype or coupling to phospholipase C underlies pregnancy adaptation of UAEC at the level of Ca(2+)signaling.
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PMID:Pregnancy-enhanced Ca2+ responses to ATP in uterine artery endothelial cells is due to greater capacitative Ca2+ entry rather than altered receptor coupling. 1689 70

Extracellular nucleotides have a profound role in the regulation of the proliferation of diseased tissue. We studied how extracellular nucleotides regulate the proliferation of LXF-289 cells, the adenocarcinoma-derived cell line from human lung bronchial tumor. ATP and ADP strongly inhibited LXF-289 cell proliferation. The nucleotide potency profile was ATP = ADP = ATPgammaS > > UTP, UDP, whereas alpha,beta-methylene-ATP, beta,gamma-methylene-ATP, 2',3'-O-(4-benzoylbenzoyl)-ATP, AMP and UMP were inactive. The nucleotide potency profile and the total blockade of the ATP-mediated inhibitory effect by the phospholipase C inhibitor U-73122 clearly show that P2Y receptors, but not P2X receptors, control LXF-289 cell proliferation. Treatment of proliferating LXF-289 cells with 100 microm ATP or ADP induced significant reduction of cell number and massive accumulation of cells in the S phase. Arrest in S phase is also indicated by the enhancement of the antiproliferative effect of ATP by coapplication of the cytostatic drugs cisplatin, paclitaxel and etoposide. Inhibition of LXF-289 cell proliferation by ATP was completely reversed by inhibitors of extracellular signal related kinase-activating kinase/extracellular signal related kinase 1/2 (PD98059, U0126), p38 mitogen-activated protein kinase (SB203508), phosphatidylinositol-3-kinase (wortmannin), and nuclear factor kappaB1 (SN50). Western blot analysis revealed transient activation of p38 mitogen-activated protein kinase, extracellular signal-related kinase 1/2, and nuclear factor kappaB1 and possibly new formation of p50 from its precursor p105. ATP-induced attenuation of LXF-289 cell proliferation was accompanied by transient translocation of p50 nuclear factor kappaB1 and extracellular signal-related kinase 1/2 to the nucleus in a similar time period. In summary, inhibition of LXF-289 cell proliferation is mediated via P2Y receptors by activation of multiple mitogen-activated protein kinase pathways and nuclear factor kappaB1, arresting the cells in the S phase.
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PMID:Adenine nucleotides inhibit proliferation of the human lung adenocarcinoma cell line LXF-289 by activation of nuclear factor kappaB1 and mitogen-activated protein kinase pathways. 1691 24

This study investigated the effect of ATP and its related signal cascades on the proliferation of mouse ESCs. ATP increased the level of [(3)H]thymidine/5-bromo-2'-deoxyuridine incorporation and the number of cells in both a time- and dose-dependent manner. AMP-CPP (a P2X(1) and P2X(3) agonist), ATP-gammaS (a P2Y agonist), and 2-methylthio-ATP (a P2X and P2Y agonist) stimulated [(3)H]thymidine incorporation. P2 purinoceptor antagonists (suramin, reactive blue 2) inhibited the ATP-induced increase in [(3)H]thymidine incorporation. Reverse transcription-polymerase chain reaction analysis revealed P2X(3), P2X(4), P2Y(1), and P2Y(2) expression in mouse ESCs. Adenylate cyclase inhibitor (SQ 22536), phospholipase C inhibitors (neomycin or U 73122), and protein kinase C (PKC) inhibitors (bisindolylmaleimide I or staurosporine) inhibited the ATP-induced increase in [(3)H]thymidine incorporation. ATP increased the level of intracellular cAMP and inositol phosphates. ATP translocated PKC alpha, delta, and zeta from the cytosol to the membrane compartment. ATP and its agonists increased [Ca(2+)](i). In addition, the ATP-induced increase in [(3)H]thymidine incorporation was completely inhibited by a combination of EGTA (extracellular Ca(2+) chelator) and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA)-AM (intracellular Ca(2+) chelator). ATP phosphorylated Akt and p44/42 mitogen-activated protein kinases (MAPKs) in a time-dependent manner, and either suramin or reactive blue 2 (RB2) blocked the ATP-induced phosphorylation of Akt. Suramin, RB2, the phosphatidylinositol 3-kinase (PI3K) inhibitor (wortmannin), or the Akt inhibitor inhibited the phosphorylation of p44/42 MAPKs. The ATP-induced increase in [(3)H]thymidine incorporation was inhibited by wortmannin, the Akt inhibitor, and the MAPK kinase inhibitor (PD 98059). Suramin, RB2, PD 98059, and wortmannin blocked the ATP-induced increase in the cyclin D1, cyclin E, cyclin-dependent kinase (CDK) 2, and CDK4 levels. In conclusion, ATP stimulates mouse ESC proliferation through PKC, PI3K/Akt, and MAPKs via the P2 purinoceptors.
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PMID:ATP stimulates mouse embryonic stem cell proliferation via protein kinase C, phosphatidylinositol 3-kinase/Akt, and mitogen-activated protein kinase signaling pathways. 1691 26

Macrophages play a key role in inflammation by synthesis and release of proinflammatory cytokines and chemokines. Extracellular nucleotides released at sites of tissue damage may be an early danger signal for immune cells, and ATP-gated P2X(7) receptors are well known to mediate the rapid release of proinflammatory IL-18 and IL-1beta. However, there is little direct evidence for the involvement of other purine receptor subtypes in the release of other cytokines or chemokines. We initially used protein arrays to address whether extracellular ATP can release cytokines and/or chemokines from rat NR8383 alveolar macrophage, which lack the P2X(7) receptor. ATPgammaS increased the release of the proinflammatory chemokine, MCP-1 (MCP-1/CCL2). Pharmacological profiling identified the receptor responsible as the P2Y(2) receptor. Brief activation (10 min) of P2Y(2) receptors increased MCP-1 mRNA levels within 30 min and increased its release at 60 min. Similar results were obtained from rat peritoneal macrophages. We investigated likely downstream signaling cascades that may be involved, specifically the canonical G(q)-mediated phospholipase C (PLC) and subsequent MAP kinase pathways, and G(i)/G(o)-mediated signaling. We could find no evidence for these pathways being involved in the P2Y(2)R-induced increase in mRNA levels although inhibition of PLC blocked the UTP-induced increased release of MCP-1. Thus, the PLC-activated pathway can account for the increased release of MCP-1, but a novel signaling pathway may be involved in the increase in MCP-1 mRNA by activation of P2Y(2) receptors in alveolar and peritoneal macrophage.
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PMID:Purinergic P2Y2 receptors induce increased MCP-1/CCL2 synthesis and release from rat alveolar and peritoneal macrophages. 1794 75

Purine and pyrimidine nucleotides have been identified as potent extracellular signalling molecules, acting at two classes of cell surface receptors, ionotropic P2X and metabotropic P2Y receptor (-R) types. Hitherto eight subtypes of the P2Y-R family have been cloned from mammalian species that exhibit sensitivity to the adenine nucleotides ATP/ADP (P2Y(1,11,12,13)), the uracil nucleotides UTP/UDP (P2Y(2,4,6) or UDP-glucose in the case of P2Y(14)) or both adenine and uracil nucleotides (P2Y(2)). The P2Y-Rs are G protein-coupled receptors activating phospholipase C via Galpha(q/11) protein and stimulating or inhibiting adenylyl cyclase via Galpha(s) and Galpha (i/o) proteins, respectively. These receptors may activate distinct signalling cascades. Although classical models predict that P2Y-Rs exist in the cell membrane as monomers, homo- or heterodimeric assemblies may be generated. Interactions with certain ion channels or ligand-gated receptors as well as the co-localization of several receptor subtypes in the same cell provide the basis for a high functional diversity. The proteins for various P2Y-Rs are expressed early in the embryonic brain and are broadly distributed on both, neurons and astroglial cells. P2Y-R involvement in the regulation of normal physiological processes on the cellular level or in vivo, such as modulation of transmitter release, generation of astroglial Ca(2+) waves, in diverse effects on behavioural functions and in the etiopathology of neurodegenerative diseases, are discussed and own data are presented. However, the exact understanding of the role of individual P2Y-R subtypes is still limited. Concerning the potentially important functions of P2Y-Rs, there is a strong need to develop stable, lipophilic and subtype-selective P2Y-R ligands, which may open new therapeutic strategies.
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PMID:P2Y receptors: focus on structural, pharmacological and functional aspects in the brain. 1797 98

Receptors for extracellular nucleotides (the P2X-calcium channels and the phospholipase C-coupled P2Y receptors) play key roles in pain signaling, but little is known on their function in trigeminal ganglia, whose hyperactivation leads to the development of migraine pain. Here we characterize calcium signaling via P2X(3) and P2Y receptors in primary mouse neuron-glia trigeminal cultures. Comparison with intact ganglion showed that, in dissociated cultures, sensory neurons retain, at least in part, their physical relationships with satellite glia. RT-PCR indicated expression of P2X(2)/P2X(3) (confirmed by immunocytochemistry) and of all cloned P2Y receptors. Single-cell calcium imaging with subtype-selective P2-agonists/antagonists revealed presence of functional neuronal P2X(3), as well as of ADP-sensitive P2Y(1,12,13) and UTP-activated P2Y(2)/P2Y(4) receptors on both neurons and glia. Calcium responses were much higher in glia, that also responded to UDP, suggesting functional P2Y(6) receptors. To study whether trigeminal ganglia P2 receptors are modulated upon treatment with pro-inflammatory agents, cultures were acutely (up to 3 min) or chronically (24 h) exposed to bradykinin. This resulted in potentiation of algogenic P2X(3) receptor-mediated calcium responses followed by their down-regulation at 24 h. At this exposure time, P2Y receptors responses in satellite glia were instead upregulated, suggesting a complex modulation of P2 receptors in pain signaling.
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PMID:Purinoceptor-mediated calcium signaling in primary neuron-glia trigeminal cultures. 1803 10

A physiological concentration of extracellular ATP stimulated biphasic Ca(2+) signal, and the Ca(2+) transient was decreased and the Ca(2+) sustain was eliminated immediately after removal of ATP and Ca(2+) in RBA-2 astrocytes. Reintroduction of Ca(2+) induced Ca(2+) sustain. Stimulation of P2Y(1) receptors with 2-methylthioadenosine 5'-diphosphate (2MeSADP) also induced a biphasic Ca(2+) signaling and the Ca(2+) sustains were eliminated using Ca(2+)-free buffer. The 2MeSADP-mediated biphasic Ca(2+) signals were inhibited by phospholipase C (PLC) inhibitor U73122, and completely blocked by P2Y(1) selective antagonist MRS2179 and protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) whereas enhanced by PKC inhibitors GF109203X and Go6979. Inhibition of capacitative Ca(2+) entry (CCE) decreased the Ca(2+)-induced Ca(2+) entry; nevertheless, ATP further enhanced the Ca(2+)-induced Ca(2+) entry in the intracellular Ca(2+) store-emptied and CCE-inhibited cells indicating that ATP stimulated Ca(2+) entry via CCE and ionotropic P2X receptors. Furthermore, the 2MeSADP-induced Ca(2+) sustain was eliminated by apyrase but potentiated by P2X(4) allosteric effector ivermectin (IVM). The agonist ADPbetaS stimulated a lesser P2Y(1)-mediated Ca(2+) signal and caused a two-fold increase in ATP release but that were not affected by IVM whereas inhibited by PMA, PLC inhibitor ET-18-OCH(3) and phospholipase D (PLD) inhibitor D609, and enhanced by removal of intra- or extracellular Ca(2+). Taken together, the P2Y(1)-mediated Ca(2+) sustain was at least in part via P2X receptors activated by the P2Y(1)-induced ATP release, and PKC played a pivotal role in desensitization of P2Y(1) receptors in RBA-2 astrocytes.
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PMID:Functional characterization of P2Y1 versus P2X receptors in RBA-2 astrocytes: elucidate the roles of ATP release and protein kinase C. 1807 86

The epithelial sodium channel (ENaC) plays a major role in the regulation of sodium balance and BP by controlling Na(+) reabsorption along the renal distal tubule and collecting duct (CD). ENaC activity is affected by extracellular nucleotides acting on P2 receptors (P2R); however, there remain uncertainties over the P2R subtype(s) involved, the molecular mechanism(s) responsible, and their physiologic role. This study investigated the relationship between apical P2R and ENaC activity by assessing the effects of P2R agonists on amiloride-sensitive current in the rat CD. Using whole-cell patch clamp of principal cells of split-open CD from Na(+)-restricted rats, in combination with immunohistochemistry and real-time PCR, we found that activation of metabotropic P2R (most likely the P2Y(2) and/or (4) subtype), via phospholipase C, inhibited ENaC activity. In addition, activation of ionotropic P2R (most likely the P2X(4) and/or (4/6) subtype), via phosphatidylinositol-3 kinase, either inhibited or potentiated ENaC activity, depending on the extracellular Na(+) concentration; therefore, it is proposed that P2X(4) and/or (4/6) receptors might function as apical Na(+) sensors responsible for local regulation of ENaC activity in the CD and could thereby help to regulate Na(+) balance and systemic BP.
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PMID:Sodium-dependent regulation of renal amiloride-sensitive currents by apical P2 receptors. 1823 98

We studied contractile effects in isolated electrically driven (1 Hz) atrial preparations from patients undergoing cardiac bypass surgery. ATP concentration dependently (10, 30, and 100 microM) and rapidly decreased force of contraction (negative inotropic effect, NIE) and thereafter more slowly increased force of contraction. The maximum positive inotropic effect (PIE) at 100 microM ATP amounted to 152% of the predrug value (n = 9) and was stable and could be washed out fast and completely. The PIE did not affect time parameters of contraction (time to peak tension and time of relaxation). Moreover, a similar NIE and PIE were noted with adenosine 5'-O-(2-thiotriphosphate) (100 microM). In contrast 2-methyl-thio-ATP did not exert a NIE but only a PIE. In a second set of experiments, preparations were first incubated for 30 min with purinoreceptor antagonists and, in their continuous presence, 100 microM ATP was applied. However, the PIE and NIE of ATP could neither be blocked with suramin (100 and 500 microM), pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (50 microM), nor reactive blue 2 (30, 100, and 500 microM), which are known blockers for subtypes of P(2) receptors, or 1,3-dipropyl-cyclopentvl-xanthine (1 and 10 microM), a subtype (A(1) adenosine) P(1) receptor blocker. Likewise, the inhibitor of phospholipase C (PLC) activity (U-73122) and the inhibitor of adenylate cyclase activity (SQ-022563) (10 microM each) failed to affect the NIE and the PIE of ATP. We tentatively suggest that the PIE of ATP might be mediated via P(2X4)-like receptors. In summary, we describe a novel biphasic effect of ATP on force contraction in the isolated human atrium. It is conceivable that ATP plays a physiological role in the human heart, for instance, after cardiac injury to sustain contractility.
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PMID:A positive inotropic effect of ATP in the human cardiac atrium. 1826 15

The inner wall of excised rat aorta was scraped by a microelectrode and Ca2+ signals were investigated by fluorescence microscopy in endothelial cells (ECs) directly coupled with injured cells. The injury caused an immediate increase in the intracellular Ca2+ concentration ([Ca2+]i), followed by a long-lasting decay phase due to Ca2+ influx from extracellular space. The immediate response was mainly due to activation of purinergic receptors, as shown by the effect of P2X and P2Y receptors agonists and antagonists, such as suramin, alpha,beta-MeATP, MRS-2179 and 2-MeSAMP. Inhibition of store-operated Ca2+ influx did not affect either the peak response or the decay phase. Furthermore, the latter was: (i) insensitive to phospholipase C inhibition, (ii) sensitive to the gap junction blockers, palmitoleic acid, heptanol, octanol and oleamide, and (iii) sensitive to La3+ and Ni2+, but not to Gd3+. Finally, ethidium bromide or Lucifer Yellow did not enter ECs facing the scraped area. These results suggest that endothelium scraping: (i) causes a short-lasting stimulation of healthy ECs by extracellular nucleotides released from damaged cells and (ii) uncouples the hemichannels of the ECs facing the injury site; these hemichannels do not fully close and allow a long-lasting Ca2+ entry.
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PMID:Ca2+ signaling in injured in situ endothelium of rat aorta. 1827 5


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