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)

The generally accepted sequence of intracellular signal transduction involves: (1) cell surface receptor-ligand interactions; (2) activation of G-proteins; (3) activation of phospholipase C, leading to inositol phosphate (IP3), and diacylglycerol production; (4) parallel mobilization of intracellular Ca2+ by IP3, and; (5) activation of protein kinase C (PKC) by diacylglycerol and Ca2+, leading to; (6) cellular responses. Human neutrophils appear to utilize this cascade, at least in general, and some, but not all, elements of the intracellular signal cascade known to be operating in intact cells also function in permeabilized cell systems. We have previously shown that permeabilized neutrophils can be induced to secrete lysosomal enzymes in response to elevated levels of Ca2+ alone and this secretion can be synergistically enhanced by the presence of guanine nucleotides. We now show that Ca2+, in the presence and absence of guanine nucleotides, can stimulate the production of soluble inositol phosphates. Furthermore, neomycin, a putative inhibitor of phospholipase C, can block Ca2(+)-induced secretion. These data thus suggest a role for phospholipase C activity or its products in the transduction process. The next enzymatic activity 'downstream' is PKC. Consequently, we looked at the role Mg-ATP, one of the substrates of PKC, plays in degranulation by permeabilized neutrophils, We found no obligatory role for this nucleotide in the secretory process. We then looked at the activity of oleoyl-acetyl-glycerol (OAG), a synthetic diacylglycerol and PKC agonist, on degranulation. We found that OAG was largely additive with Ca2+. Another PKC agonist, phorbol myristate acetate (PMA), also did not display notable synergy. Finally, inhibitors of PKC activity were not capable of blocking secretion, either in the presence or absence of guanine nucleotides. Thus, while circumstantial evidence seems to point towards a requirement for phospholipase C activation and diacylglycerol production in secretion, we were unable to demonstrate the next putative step in signal transduction, namely activation of PKC.
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PMID:Protein kinase C is not involved in secretion by permeabilized human neutrophils. 264 83

The binding of the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine to its cell surface receptor rapidly elicits the hydrolysis of phosphatidylinositol 4,5-bisphosphate by phospholipase C to form the putative second messengers inositol 1,4,5-trisphosphate and sn-1,2-diacylglycerol. To investigate the possible role of a guanine nucleotide binding protein in transduction of this membrane signal, we examined the effects of pertussis toxin on chemotactic peptide-stimulated inositol phospholipid metabolism in differentiated HL-60 cells labeled with [3H]inositol. Pertussis toxin inhibited the chemotactic tripeptide-stimulated production of inositol mono-, bis-, and trisphosphates and secretion of N-acetyl-beta-D-glucosaminidase in a time- and concentration-dependent manner. Treatment with pertussis toxin did not alter the total incorporation or the distribution of [3H]inositol in inositol phospholipid. Chemotactic peptide receptor number was unchanged, although a slight decrease in binding affinity was observed. These findings suggest a role for a guanine nucleotide binding protein in coupling the chemotactic peptide receptor to phospholipase C.
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PMID:Pertussis toxin inhibits chemotactic peptide-stimulated generation of inositol phosphates and lysosomal enzyme secretion in human leukemic (HL-60) cells. 286 Jun 68

It is very well established that the principal control of salivary secretion is derived from autonomic innervation. Transmission of a neural signal to a salivary gland acinar cell occurs chemically via neurotransmitters, the first messengers of a secretory response. Neurotransmitters bind to specific cell surface receptor proteins, an event which activates precise transduction mechanisms which then transfer the neural signal to the inside of the cell. There are two major transduction mechanisms operative in salivary gland acinar cells. One involves the generation of cAMP, the other involves the breakdown of plasma membrane polyphosphoinositides. For both mechanisms, the appropriate stimulated receptor activates a second plasma membrane protein, termed an N (or G) protein. The N protein requires GTP to activate an enzyme (adenylate cyclase or phospholipase C), which then catalyzes the formation of a second messenger (cAMP and inositol trisphosphate/diacylglycerol, respectively). This action provides the intracellular signal for secretory events (protein, fluid, electrolyte secretion) to begin.
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PMID:Neurotransmitter control of secretion. 288 3

Prostaglandins inhibit the proliferation of the murine P815 mastocytoma. The mechanism of this antitumour activity remains undefined. In several cell systems, the action of PGs is inhibited at the cell surface receptor by pertussis toxin likely through regulatory G proteins involved in the inhibition of adenyl cyclase or activation of phospholipase C. We therefore determined the effect of prostaglandins on the biochemical consequences of activation of these pathways; i.e. concentrations of cyclic AMP (cAMP) and cytosolic free Ca+2 concentrations [( Ca/2]i) respectively. PGD2 (6 ug/mL), PGE1 (10 ug/mL) and PGB1 (50 ug/mL) maximally inhibited (3H)-thymidine incorporation to DNA. PGF2 alpha did not affect DNA synthesis. PGE1 (10 ug/mL) induced a three fold increase in cAMP concentrations. In contrast, the other prostaglandins did not alter cAMP concentrations. Maximal growth inhibitory doses of PGD2, PGE1 and PGB1 decrease [Ca+2]i, as measured by the fluorescence of Indo-1, from 320 +/- 5 nM to 172 +/- 20 nM, 161 +/- 12 nM, and 151 +/- 18 nM respectively. PGF2 alpha did not alter [Ca+2]i. Therefore, in contrast to the effects on cAMP, the decrease in [Ca+2]i was concordant with the inhibition of DNA synthesis. This suggests that PGs may inhibit proliferation through decreasing [Ca+2]i in the P815 mastocytoma.
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PMID:Prostaglandins inhibit proliferation of the murine P815 mastocytoma by decreasing cytoplasmic free calcium levels [( Ca+2]i). 314 77

Utilizing a digitonin-permeabilized cell system, we have studied the release of calcium from a non-mitochondrial intracellular compartment in cultured human fibroblasts (HSWP cells). Addition of 1 mM MgATP to a monolayer of permeabilized cells in a cytosolic media buffered to 150 nM Ca with EGTA rapidly stimulates 45Ca uptake, and the subsequent addition of the putative intracellular messenger inositol trisphosphate (InsP3) induces rapid release of 85% (+/- 6% n = 6) of the 45Ca taken up in response to ATP. Mitogenic peptides (bradykinin, vasopressin, epidermal growth factor [EGF], and insulin) and orthovanadate, which are effective in mobilizing intracellular Ca in intact cells, have little or no effect when added alone to permeabilized cells. However, in the presence of GTP these agents stimulate accumulation of inositol phosphates and release Ca from the InsP3-sensitive pool. These data suggest that a GTP binding protein is involved in receptor mediated activation of phospholipase C, which leads to release of inositol phosphates. The GTP-dependent release of InsP3 and the mobilization of 45Ca from the intracellular compartment are inhibited by pretreatment of cells, prior to permeabilization, with the protein kinase C activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA). TPA pretreatment does not affect the InsP3 stimulated Ca release. These results suggest that protein kinase C is involved in down-regulation or inhibition of phospholipase C, or the GTP binding protein responsible for relaying the mitogenic signal from the cell surface receptor to the phospholipase C activity.
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PMID:Calcium mobilization in permeabilized fibroblasts: effects of inositol trisphosphate, orthovanadate, mitogens, phorbol ester, and guanosine triphosphate. 349 99

Mineral ion homeostasis in mammalian species is maintained by a complex mechanism comprising sensors of the extracellular calcium concentration (Ca2+0) (i.e. parathyroid cells) as well as effectors that modify their translocation of mineral ions into and out of the extracellular fluid (e.g. kidney) in response to calciotropic hormones. Indirect evidence accumulated over the past decade suggested that parathyroid cells sense Ca2+0 through a cell surface receptor coupled to intracellular second messenger systems via one or more guanine nucleotide regulatory (G) proteins. More recently, Brown et al. employed expression cloning in Xenopus laevis oocytes to isolate a cDNA encoding a Ca2+0-sensing receptor from bovine parathyroid. The expressed receptor activates phospholipase C in a G-protein dependent manner and shows pharmacological properties almost identical to those of the native parathyroid receptor. Agonists for the receptor include not only divalent cations (e.g. Ca2+ and Mg2+) but also trivalent cations and even organic polycations such as neomycin. The deduced amino acid sequence of the cloned receptor confirms that it is a member of the superfamily of G-protein-coupled receptors. Receptor transcripts are present in parathyroid as well as in kidney, thyroid and brain. Therefore, this receptor may mediate the sensing of Ca2+0 not only by parathyroid cells but also by other tissues directly regulated by Ca2+0 (e.g. the thyroidal C cells and certain kidney cells) as well as those not currently known to be involved in calcium homeostasis (viz. in the brain).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular mechanisms underlying the sensing of extracellular Ca2+ by parathyroid and kidney cells. 774 89

The release of arachidonic acid by phospholipases in response to cell surface receptor activation may be an important step in the initiation of inotropic events in cardiac muscle. Endothelin has been shown to activate phospholipase A2 and release arachidonic acid in isolated rat hearts. Endothelin also has a positive inotropic effect in cardiac muscle, suggesting that endothelin increases Ca2+ influx or the amount of Ca2+ released from the sarcoplasmic reticulum. We used suspensions of adult rat ventricular myocytes loaded with fura-2/AM to compare the effects of arachidonic acid and endothelin on Ca2+ transients evoked by extracellular ATP. We showed recently (Damron, D.S., and Bond, M. (1993) Circ. Res. 72, 376-386) that pretreatment of cardiac myocytes with arachidonic acid significantly potentiated the amplitude of the ATP-triggered Ca2+ transient. We now report that endothelin also enhances the ATP-triggered Ca2+ transient and that the effect of the combination of maximal doses of endothelin and arachidonic acid is additive. Neither endothelin nor arachidonic acid was found to affect the size of the sarcoplasmic reticulum Ca2+ store. The potentiating effects of both arachidonic acid and endothelin were sensitive to inhibitors of protein kinase C. Endothelin was also found to stimulate phospholipase C but not phospholipase A2. Application of arachidonic acid to individual cardiac muscle cells resulted in inhibition of the transient outward K+ current, whereas application of endothelin inhibited the delayed rectifier current. These effects of arachidonic acid and endothelin were additive, and both effects could be blocked by the protein kinase C inhibitor, staurosporine. Similarly, staurosporine inhibited endothelin-induced increases in isometric contractions in ventricular papillary muscle. We conclude that arachidonic acid and endothelin may be involved in the modulation of inotropic activity in cardiac muscle by means of protein kinase C-dependent inhibition of two distinct K+ channels. This would result in a prolongation of action potential duration and thus an increase in Ca2+ influx across the sarcolemma.
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PMID:Arachidonic acid and endothelin potentiate Ca2+ transients in rat cardiac myocytes via inhibition of distinct K+ channels. 826 73

Ligation of CD38 inhibits proliferation and induces apoptosis of human immature B cells, but the molecular mechanisms underlying this function are unknown. We found that CD38 dimerization with the specific mAbs T16 and IB4 induces rapid and transient tyrosine phosphorylation of several intracellular proteins in the immature B cell lines RS4;11, REH, 380, Nalm6, and OP-1. This effect could be markedly reduced by incubating cells with the tyrosine kinase inhibitors genistein, staurosporine, and herbimycin A. CD38 dimerization induced tyrosine phosphorylation of the protein kinase syk and increased syk kinase activity. CD38 dimerization also induced tyrosine phosphorylation of phospholipase C-gamma and of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-K). The latter was accompanied by a distinct increase in PI 3-kinase activity in the immunoprecipitates obtained with an anti-phosphotyrosine Ab. In contrast to the signaling triggered by surface Ig engagement in B lymphocytes, CD38 ligation did not appear to induce tyrosine phosphorylation of the src-like protein tyrosine kinases lyn, fyn, and btk, or of vav- and ras-GTPase-activating protein, nor did it induce detectable changes in cytosolic CA2+ concentrations. CD38 signaling also differed from cytokine-induced signaling in that it did not cause tyrosine phosphorylation of Jak1 and Jak2. Finally, CD38 ligation did not inhibit IL-3-induced tyrosine phosphorylation of Jak2. These results identify CD38 as a cell surface receptor with signal transduction properties activated by dimerization. Induction of signal transduction by CD38 ligation implies the existence of a yet unidentified natural ligand of CD38.
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PMID:CD38 signal transduction in human B cell precursors. Rapid induction of tyrosine phosphorylation, activation of syk tyrosine kinase, and phosphorylation of phospholipase C-gamma and phosphatidylinositol 3-kinase. 859 49

The recent cloning of an extracellular calcium (Ca2+o)-sensing receptor (CaR) from the parathyroid gland and the kidney has provided novel insights into the mechanisms that underlie the direct actions of Ca2+o on various cells. The receptor is a member of the superfamily of G protein-coupled receptors, activating phospholipase C (PLC) and probably also inhibiting adenylate cyclase in target tissues. In the parathyroid gland it is a key mediator of the inhibition by high Ca2+o of parathyroid hormone (PTH) secretion and, perhaps, PTH gene expression and parathyroid cellular proliferation. It also appears to represent the major mechanism through which Ca2+o stimulates the secretion of calcitonin from the thyroidal C-cells. In the kidney, the CaR directly inhibits tubular reabsorption of calcium and magnesium in the thick ascending limb, and may be responsible for the long-recognized, but poorly understood inhibition of urinary concentrating ability by hypercalcemia. The demonstration that activating and inactivating mutations of the CaR, respectively, are the proximate causes of the inherited hypocalcemic disorder, autosomal dominant hypocalcemia (ADH) and the hypercalcemic diseases, familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), has provided additional strong support for the physiologic importance of the CaR in human mineral ion homeostasis. Therefore, when Ca2+o acts through its own G protein-coupled cell surface receptor, it acts as an extracellular first messenger in addition to serving its better recognized role as a key intracellular second messenger.
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PMID:The First Annual Bayard D. Catherwood Memorial Lecture. Ca2+-receptor-mediated regulation of parathyroid and renal function. 878 75

Previously, we identified peptides that stimulate phosphoinositide hydrolysis in several leukocyte cell lines from mixtures of random hexapeptide sequences. Moreover, the peptides activate phospholipase C via a pertussis toxin-sensitive G protein-coupled receptor. We now investigate the structure-activity relationship of the peptides with the goal of improving the activity of the peptides, as well as the biologic function of the peptides. Substitution of the L-methionine at the C terminus of peptides with D-methionine markedly increased the effectiveness of the peptides. The half-maximal effective concentrations of MKYMPm-NH2 and WKYMVm-NH2 for stimulation of phosphoinositide hydrolysis in U266 cells were 30 and 0.5 nM, respectively. By BIAcore analysis we confirmed the existence of a receptor for WKYMVm-NH2. Furthermore, the intracellular calcium concentration increase induced by WKYMVm-NH2 was not inhibited by several chemoattractants (FMLP, IL-8, platelet-activating factor, C5a, granulocyte-macrophage CSF, and granulocyte CSF) suggests that WKYMVm-NH2 has a unique cell surface receptor on leukocytes. WKYMVm-NH2 stimulated the phosphoinositide hydrolysis in U937, HL60, and U266 cells, as well as in human neutrophils. Moreover, WKYMVm-NH2 is more effective than FMLP in the production of superoxide in human neutrophils. The data suggest that WKYMVm-NH2 may have the ability to activate the microbicidal functions of human neutrophils.
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PMID:A peptide with unique receptor specificity: stimulation of phosphoinositide hydrolysis and induction of superoxide generation in human neutrophils. 902 31


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