Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells from brain microvessels (BCEC) express high affinity receptor sites for endothelin-1 that recognize endothelin-3 with a low affinity (Vigne, P., Marsault, R., Breittmayer, J.P. & Frelin, C. (1990) Biochem. J. 266, 415-420). Binding experiments using 125I-endothelin-3 showed the presence in BCEC of a new class of receptor sites that had a high affinity for endothelin-3 (Kd = 0.8 nM), endothelin-1 (Kd = 0.8 nM), and sarafotoxin S6b (Kd = 0.3 nM). Endothelins activated phospholipase C in BCEC and produced transient increases in intracellular Ca2+ with properties of a low affinity endothelin-3 receptor. Endothelins also increased 22Na+ uptake via the Na+/H+ antiporter in BCEC. Concentrations for half-maximum activation (endothelin-1, 0.5 nM; sarafotoxin S6b, 1 nM; endothelin-3, 2 nM) were close to the Kd values determined in 125I-endothelin-3-binding experiments. The action of endothelins on Na+/H+ exchange was not mimicked by phorbol myristate acetate, it was not reversed by staurosporine, and it did not correlate with the phosphorylation of the 80-kDa protein. These results indicated that the action of endothelins on Na+/H+ exchange did not involve protein kinase C. It is concluded that BCEC coexpress two types of functional receptor sites for endothelins: (i) a high affinity endothelin-1, low affinity endothelin-3 receptor that is coupled to phospholipase C and to intracellular Ca2+ mobilization, and (ii) a high affinity endothelin-1, high affinity endothelin-3 receptor that controls Na+/H+ exchange activity via a protein kinase C-independent mechanism.
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PMID:Endothelins activate Na+/H+ exchange in brain capillary endothelial cells via a high affinity endothelin-3 receptor that is not coupled to phospholipase C. 184 60

We have isolated a hamster fibroblast cDNA clone that encodes a serotoninergic receptor whose deduced amino acid sequence displays 94% identity with the rat brain serotonin (5-HT) type 2 receptor. When expressed in Xenopus oocytes, the hamster receptor efficiently couples to the phosphoinositide second messenger system and leads to intracellular Ca2+ mobilization in response to 5-HT. To determine the pharmacological properties of this receptor, and to evaluate the role of phospholipase C (PLC) activation in growth modulation by 5-HT, we have expressed it in hamster fibroblasts. Transfected cells that express 5-HT receptors were selected using a novel method based on coexpression of the Na+/H+ antiporter gene as a selectable marker. After co-transfection of the 5-HT receptor and Na+/H+ antiporter cDNAs in fibroblasts lacking antiporter activity (variants of the CCL39 line), 50% of the clones resistant to an acute acid load express functional receptors. The pharmacological profile of the transfected receptor is consistent with it being of the 5-HT2 subtype, and the extent of 5-HT-stimulated PLC activation in independent clones correlates with their relative level of cRNA expression. In cells in where addition of 5-HT leads to strong activation of PLC, and inhibition of adenylate cyclase via endogenous 5-HT1b receptors, 5-HT alone has little effect on DNA synthesis stimulation. Thus we conclude that activation of the PLC signalling pathway in these cells is not sufficient to trigger G0/G1 to S phase transition. Strong activation of PLC via 5-HT2 receptors does however contribute to the synergy observed between 5-HT (Gi-coupled pathway) and fibroblast growth factor (tyrosine kinase-activated pathway) on DNA synthesis reinitiation in transfected cells.
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PMID:Cloning, functional expression and role in cell growth regulation of a hamster 5-HT2 receptor subtype. 194 95

Hemopoietic cells have an absolute requirement for survival and proliferation for specific growth factors. The growth factors maintain the critical vitality of the cells by stimulating adenosine triphosphate (ATP) synthesis and hexose transport. Intracellular alkalinization also occurs rapidly through the stimulation of the Na+/H+ antiporter. These immediate metabolic events, not initiated by serum components, appear to be necessary for the integrity of cellular viability (Fig. 6). Interleukin-3 has been shown to induce the activation of PK-C through a mechanism(s) not requiring the hydrolysis of phosphoinositol 4,5 bisphosphate. A role for Ca2+ influx or intracellular release in the action of CSFs or interleukins has not been shown. Although downregulation of cAMP has been reported in response to IL-2, the signal transduction process of CSFs and IL-2 appears not to be mediated by upregulation of cyclic nucleotide metabolism or "classical" phospholipid degradative pathways. Protein phosphorylation is clearly modulated by the hemopoietic cytokines, yet only the CSF-1 receptor has any known intrinsic kinase activity. Instead, the IL-3, GM-CSF receptors, and perhaps G-CSF appear to be coupling to kinases of both tyrosine and serine specificities. This may be a direct allosteric interaction with membrane-associated kinases or transduced through an intermediate protein such as those using GTP. Such is the case for many hormone receptors that couple to amplifying "second messenger" enzyme systems (i.e., adenylate cyclase, phospholipase C) or members of the insulin growth factor family that couple to tyrosine kinases in proximity to the receptors (IGF-II). One of the kinase systems that IL-2, IL-3, and other CSFs stimulate appears to have some characteristics similar to PK-C. Direct activators of PK-C stimulate some similar serine-threonine phosphorylation and perhaps even tyrosine phosphorylation. The hemopoietic growth factors, however, stimulate tyrosine phosphorylation of some proteins that are not phosphorylated in response to PK-C activators, suggesting that these kinase systems are independently regulated. Although phorbol esters stimulate many of the same metabolic activities (ATP synthesis in myeloid and lymphoid cell lines), growth-factor abrogation is clearly associated with the action of tyrosine kinase oncogenes or the nuclear oncogene effectors such as v-myc. It is likely, therefore, that tyrosine kinases are playing a critical role in the control of proliferation although the dominant amount of cellular protein phosphorylations are on serine. Both classes of kinases are apparently required for growth-factor action. All the hemopoietic growth factors examined thus far stimulate the steady-state accumulation of the nuclear protooncogenes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hematopoietic growth-factor signal transduction and regulation of gene expression. 209 Feb 58

The effects of Li+ on signal transduction in dibutyryl cAMP-differentiated HL-60 cells were studied. Upon differentiation, these human promyelocytic leukemia cells express a chemotactic formyl peptide receptor, which is coupled through a guanine nucleotide-binding protein to phospholipase C. Stimulation with fMet-Leu-Phe results in changes in intracellular pH which are thought to be mediated by protein kinase C regulation of Na+/H+ antiporter function. Acute LiCl treatment (10 mM) was without any effect on Na+/H+ activity. However, pretreatment of HL-60 cells with 1 or 10 mM LiCl for at least 5 days resulted in a marked attenuation of fMet-Leu-Phe effects on Na+/H+ activity. In undifferentiated HL-60 cells, which lack fMet-Leu-Phe receptors, intracellular acidification induced by the proton ionophore nigericin generates an alkalinization response. Chronic (but not acute) Li+ treatment also resulted in an inhibition of the nigericin-mediated response. Furthermore, stimulation of the Na+/H+ antiporter by the phorbol ester, phorbol-12-myristate-13-acetate, was also markedly attenuated by chronic LiCl treatment, suggesting an impairment of protein kinase C activity. In contrast, fMet-Leu-Phe-induced increases in intracellular Ca2+ and phospho-inositide breakdown were unchanged in cells treated with Li+ for 5 days. These results indicate that chronic but not acute Li+ treatment alters intracellular pH regulation possibly at a site distal to the fMet-Leu-Phe receptor.
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PMID:Chronic Li+ attenuates agonist- and phorbol ester-mediated Na+/H+ antiporter activity in HL-60 cells. 216 72

Growth of Chinese hamster lung fibroblasts (CCL39) on thrombin as sole mitogen is dependent on phosphatidylinositol (PI) metabolism and activation of the Na+/H+ antiporter. By modifying a H+ suicide selection developed for the isolation of antiporter mutants in these cells, we enriched for and isolated CCL39 variants deficient in the thrombin mitogenic response (thrombin nongrowers). These mutants retain alternate mitogenic mechanisms and, hence, grow well on media containing serum. When challenged with thrombin, the mutants show decreased, increased, or unchanged levels of inositol phosphates produced as compared with wild type cells. One of the mutants (D1-6b) has decreased inositol phosphates production not only with thrombin but also with serotonin (5-hydroxytryptamine) and AlF4-, suggesting a defect distal to the thrombin receptors. Extracts of this mutant reveal marked decreased phospholipase C activity toward PI. From the different phenotypes of the thrombin nongrowers, it is clear that the selection is general and that mutants with various biochemical defects should lead to a better understanding of the PI cycle as well as of functions essential to mitogenesis.
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PMID:Hamster fibroblasts defective in thrombin-induced mitogenesis. A selection for mutants in phosphatidylinositol metabolism and other functions. 276 25

Stimulation of platelets with thrombin, ADP and epinephrine has recently been shown to activate a Na+/H+ antiporter, with a resulting alkalinization of the cytoplasm. Unlike thrombin, however, epinephrine is incapable of directly activating phospholipase C, but is well known to potentiate the effects of thrombin on this enzyme and other subsequent steps of platelet activation. Therefore, we have studied the involvement of the Na+/H+ antiporter in this aspect of epinephrine action to see whether alkalinization of platelet cytosol could be a requirement for agonists to stimulate inositol phospholipid hydrolysis and mobilize cellular Ca2+ stores. Alpha-thrombin induced the rapid formation of inositol trisphosphate with a parallel mobilization of intracellular Ca2+ stores. Epinephrine alone had no effect on either of these parameters. The response to thrombin desensitized over a period of minutes, and after this had occurred, epinephrine was able to activate phospholipase C and induce the release of intracellular Ca2+. This showed that epinephrine was able to recouple thrombin receptors to phospholipase C, and this appeared to be mediated by the same mechanism which is involved in potentiation by epinephrine of thrombin-stimulation of phospholipase C. These effects of epinephrine were not altered by inhibition of the Na+/H+ antiporter with ethylisopropylamiloride or by use of the Na+/H+ ionophore, monensin. We conclude that epinephrine potentiates thrombin-induced responses by a mechanism which is unrelated to its effects on the Na+/H+ antiporter, and this is not a requirement for thrombin-induced phospholipase C activation.
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PMID:The Na+/H+ antiporter is not involved in potentiation of thrombin-induced responses by epinephrine. 283 79

We have shown previously that normal human neutrophils triggered by immune complexes displayed significant levels of cytotoxicity towards non-sensitized target cells (non-specific cytotoxicity-NSC) (Geffner, J. R. et al. 1987). Despite the fact that NSC and antibody-dependent cellular cytotoxicity (ADCC) are both mediated through neutrophil Fc gamma R and require the activation of the respiratory burst, the cytolytic mechanisms involved in each case appear to be different. In order to analyse the pathways of activation involved in the induction of NSC and ADCC, we studied here some of the metabolic requirements associated with each cytotoxic function. Our results suggest that ADCC is dependent on Na+/H+ antiporter activity, de novo protein synthesis, availability of external Ca2+ and calmodulin activity, activation of phospholipase C and activation of protein kinase C. On the other hand, NSC appears to be dependent on availability of external Ca2+ and calmodulin activity and activation of phospholipase A2. These results indicate that different pathways of activation are involved in the induction of neutrophil-mediated ADCC and NSC.
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PMID:Different activation pathways involved in antibody-dependent and immune-complexes-triggered cytotoxicity mediated by neutrophils. 285 17

Data in the previous paper suggest that epinephrine can mobilize a small pool of arachidonic acid via an enzymatic pathway distinct from phospholipase C and that this pathway is blocked by perturbations that block Na+/H+ exchange. The present studies demonstrate that epinephrine and ADP stimulate a phosphatidylinositol-hydrolyzing phospholipase A2 activity in human platelets. This occurs even when measurable phospholipase C activation, platelet secretion, and secondary aggregation are blocked with the thromboxane A2 receptor antagonist SQ29548. Furthermore, perturbants of Na+/H+ exchange diminish lysophosphatidylinositol production in response to epinephrine, ADP, and thrombin, but not to the Ca2+ ionophore A23187. Artificial alkalinization of the platelet interior with methylamine reverses the effect of the Na+/H+ antiporter inhibitor, ethylisopropylamiloride, on thrombin-stimulated lysolipid production, suggesting that the alkalinization of the platelet interior which would occur secondary to activation of Na+/H+ exchange might play an important role in phospholipase A2 activation. In addition, treatment of platelets with methylamine increases the sensitivity of phospholipase A2 to activation by the Ca2+ ionophore A23187, suggesting that changes in pH and Ca2+ may regulate phospholipase A2 activity synergistically. Finally, epinephrine causes a prompt decrease in platelet-chlortetracyclin fluorescence even in the presence of cyclooxygenase inhibitors, suggesting that epinephrine is able to mobilize membrane-bound Ca2+ independent of phospholipase C activation. Taken together, the data suggest that epinephrine-provoked stimulation of phospholipase A2 activity may occur as a result of Ca2+ mobilization and a concomitant intraplatelet alkalinization resulting from accelerated Na+/H+ exchange.
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PMID:Evidence that Na+/H+ exchange regulates receptor-mediated phospholipase A2 activation in human platelets. 301 59

As was shown in our previous work, the intracellular pH (pHi) of cultured human fibroblasts depends on cell density. The pHi is low in single cells, higher in cells, forming small groups and maximal in a sparse monolayer. On the other hand, the pHi is low in areas of confluent monolayers. In the present work, we show that the effects of inhibitors of various pH-controlling mechanisms as well as inhibitors of key enzymes in signal transduction pathways depend on the local cell density. We have found that N-ethylmaleimide and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole, known as inhibitors of V-type H+ ATPase, inhibit the elevation of pHi induced by cell-cell contact interactions; meanwhile Cd2+ ions, which inhibit H+ conductive pathway, cause an increase of pHi in a confluent monolayer. Our data revealed also that the Na+/H+ antiporter does not play an essential role in the pHi regulation by intercellular contacts. Inhibitors of phospholipase A2 (4-bromophenacyl-bromide), phospholipase C (neomycin) and protein kinase C (H-7) dramatically change the way the pHi is modulated by local cell density. It is suggested that cell-cell interactions regulate cell activities via modulation of pHi, which is under positive control from phospholipase A2 and under negative control from protein kinase C.
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PMID:Regulation of intracellular pH by cell-cell adhesive interactions. 758 3

The interference of several new hexadecylphosphocholine analogues with mitogenic signal transduction was investigated in NIH3T3 fibroblasts by studying the effects of these agents on thrombin-induced inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) formation and the subsequent Ca2+ release, on protein kinase C (PKC) in cell-free extracts, on the PKC-mediated activation of the Na+/H+ antiporter and on c-fos induction. The compounds investigated include hexadecylphosphocholine (HePC), octadecyl-[2-(N-methyl-piperidinio)-ethyl]-phosphate (D20133), octadecyl-(N,N-dimethyl-piperidinio-4-yl)-phosphate (D21266); octadecyl-[2-(trimethyl-arsonio)-ethyl]-phosphate (D21805) and hexadecylphospho-L-serine (HePS). The data indicate that (i) all compounds inhibit the thrombin-induced progression of growth-arrested NIH3T3 cells into S phase with similar IC50 values; (ii) the common denominator of all compounds is a reduction of Ins(1,4,5)P3 formation, resulting in an attenuation of Ca2+ release; (iii) the direct interaction with PKC does not significantly contribute to the antitumor activity of these agents; (iv) the new HePC congeners D21266, D21133 and D21805 affect the same targets as HePC, i.e. PKC and phosphatidylinositol 4,5-bisphosphate-specific phospholipase C (PLC). The lower toxicities of these compounds cannot be explained by a less pronounced inhibition of PKC or PLC, respectively.
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PMID:Interference of new alkylphospholipid analogues with mitogenic signal transduction. 763 30


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