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)

Kazinol B, a natural isoprenylated flavan, stimulated the [Ca(2+)](i) elevation in the presence or absence of Ca(2+) in the medium. Treatment with chymotrypsin or phorbol 12-myristate 13-acetate to shedding of L: -selectin had no effect on subsequent kazinol B-induced Ca(2+) response. Upon initial cyclopiazonic acid (CPA) treatment in the absence of external Ca(2+), the subsequent [Ca(2+)](i) rise followed by challenge with kazinol B was greatly diminished. The ryanodine receptor blockers, 8-bromo-cyclic ADP-ribose and ruthenium red did not affect kazinol B-evoked Ca(2+) release from internal stores. However, the inhibitors of sphingosine kinase, dimethylsphingosine, but not dihydrosphingosine, inhibited kazinol B-induced Ca(2+) release. Kazinol B-induced [Ca(2+)](i) rise was not affected by two nitric oxidase inhibitors, N-(3-aminomethyl)benzylacetamidine (1400W) and 7-nitroindazole, cytochalasin B and Na(+)-deprivation. This response was slightly attenuated by 2-aminoethyldiphenyl borate (2-APB), a D: -myo-inositol 1,4,5-trisphosphate (IP(3)) receptor blocker, and by genistein, a general tyrosine kinase inhibitor. However, the Ca(2+) response was greatly diminished by two actin filament reorganizers, calyculin A and jasplakinolide, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY 294002), an inhibitor of phosphoinositide 3-kinase, N-(3-aminomethyl)benzylacetamidine (SB 203580), the p38 mitogen-activated protein kinase inhibitor, 1-[6-[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122), the inhibitor of phospholipase C-coupled processes, and by 0.3 mM La(3+) or Ni(2+). Kazinol B did not evoke any appreciable Ba(2+) and Sr(2+) entry into cells. The Ca(2+) entry blockers, 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole (SKF-96365), but not cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL-12,330A), inhibited a kazinol B-induced [Ca(2+)](i) rise. Kazinol B had no effect on the pharmacologically isolated plasma membrane Ca(2+)-ATPase activity. In a Ca(2+)-free medium, kazinol B inhibited the subsequent Ca(2+) addition, resulting in robust entry in CPA- and formyl peptide-activated cells. Kazinol B produced a concentration-dependent reduction in the mitochondrial membrane potential. These results indicate that kazinol B stimulates Ca(2+) release from internal Ca(2+) store, probably through the sphingosine 1-phosphate and IP(3) signaling, and activates external Ca(2+) influx mainly through a non-store-operated Ca(2+) entry (non-SOCE) pathway. Inhibition of SOCE by kazinol B is probably attributable to a break in the Ca(2+) driven force of mitochondria.
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PMID:Stimulation of cellular free Ca2+ elevation and inhibition of store-operated Ca2+ entry by kazinol B in neutrophils. 1555 42

Fertilization elicits a dramatic, transient rise in Ca2+ within the egg which is an essential component of egg activation and consequent initiation of development. In the sea urchin egg, three distinct Ca2+ stores have been identified which could, either individually or in combination, initiate Ca2+ release at fertilization. Inositol 1,4,5-trisphosphate (IP3) production by phospholipase C (PLC) has been suggested as the singular signal in initiating the Ca2+ transient. Other studies indicate that Ca2+ stores gated by cyclic adenosine diphosphate ribose (cADPR) or nicotinic acid adenine dinucleotide phosphate (NAADP) are also necessary. We have examined the temporal relationship between the Ca2+ rise and IP3 production at fertilization in vivo within individual eggs using a green fluorescent protein (GFP) coupled to a pleckstrin homology (PH) domain that can detect changes in IP3. Translocation of the probe occurred after the Ca2+ rise was initiated. Earlier, and possibly smaller, IP3 changes could not be excluded due to limitations in probe sensitivity. High IP3 levels are maintained during the decline in cytoplasmic Ca2+, suggesting that later IP3 metabolism might not be related to regulation of Ca2+, but may function to modulate other PIP2 regulated events such as actin polymerization or reflect other novel phosphoinositide signaling pathways.
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PMID:Phosphoinositide metabolism at fertilization of sea urchin eggs measured with a GFP-probe. 1560 87

Rat neutrophils express the mRNA encoding for transient receptor potential (TRP) V1. However, capsaicin-stimulated [Ca2+]i elevation occurred only at high concentrations (> or = 100 microM). This response was substantially decreased in a Ca2+-free medium. Vanilloids displayed similar patterns of Ca2+ response with the rank order of potency as follows: scutigeral>resiniferatoxin>capsazepine>capsaicin=olvanil>isovelleral. Arachidonyl dopamine (AAD), an endogenous ligand for TRPV1, failed to desensitize the subsequent capsaicin challenge. Capsaicin-induced Ca2+ response was not affected by 8-bromo-cyclic ADP-ribose (8-Br-cADPR), the ryanodine receptor blocker, but was slightly attenuated by 1-[6-[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122), the inhibitor of phospholipase C-coupled processes, 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole (SKF-96365), the blocker of receptor-gated and store-operated Ca2+ (SOC) channels, 2-aminoethyldiphenyl borate (2-APB), the blocker of D-myo-inositol 1,4,5-trisphospahte (IP3) receptor and Ca2+ influx, and by ruthenium red, a blocker of TRPV channels, and enhanced by the Ca2+ channels blocker, cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL-12330A) and Na+-deprivation. In addition, capsaicin had no effect on the plasma membrane Ca2+-ATPase activity or the production of nitric oxide (NO) and reactive oxygen intermediates (ROI) or on the total thiols content. Capsaicin (> or = 100 microM) inhibited the cyclopiazonic acid (CPA)-induced store-operated Ca2+ entry (SOCE). In the absence of external Ca2+, the robust Ca2+ entry after subsequent addition of Ca2+ was decreased by capsaicin in CPA-activated cells. Capsaicin alone increased the actin cytoskeleton, and also increased the actin filament content in cell activation with CPA. These results indicate that capsaicin activates a TRPV1-independent non-SOCE pathway in neutrophils. The reorganization of the actin cytoskeleton is probably involved in the capsaicin inhibition of SOCE.
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PMID:Capsaicin stimulates the non-store-operated Ca2+ entry but inhibits the store-operated Ca2+ entry in neutrophils. 1588 82

1. Agonist interaction with phospholipase C-linked receptors at the plasma membrane can elicit both Ca2+ and Na+ influxes in lymphocytes. While Ca2+ influx is mediated by Ca2+ release-activated Ca2+ (CRAC) channels, the pathway responsible for Na+ influx is largely unknown. 2. We show that thapsigargin, ionomycin, ADP-ribose and IP3 activated a nonselective cation channel in lymphocytes that had a slightly outwardly rectifying I-V relationship, and a single channel conductance of 23.1 pS. We termed this channel a Ca2+ release-activated nonselective cation (CRANC) channel. 3. On activation in cell-attached configuration, switching to an inside-out configuration abolished CRANC channel activity. 4. Transfection of Jurkat T cells with antisense oligonucleotides for LTRPC2 reduced capacitative Ca2+ entry. 5. These results suggest that CRANC channels are responsible for the Na+ influx as well as a portion of the Ca2+ influx in lymphocytes induced by store depletion, that sustained activation of CRANC channels requires some property of the environment of a cell depleted of its Ca2+ stores; and that LTRPC2 protein is a likely component of the CRANC channel.
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PMID:A store-operated nonselective cation channel in human lymphocytes. 1607 82

Mono-ADP-ribosyltransferase (ART) 4 belongs to a family of ectoenzymes that catalyze the transfer of ADP-ribose from NAD+ to a target protein. ART4 could be detected on HEL cells and erythrocytes by FACS analysis while it was absent from activated monocytes, despite the presence of ART4 mRNA in these cells. The predicted glycosylphosphatidylinositol (GPI) linkage of ART4 could be verified by showing that treatment of erythrocytes, HEL cells and ART4-transfected HEK-293-T cells with phosphatidylinositol-specific phospholipase C results in a decrease in ART4 expression. Furthermore, an ART4 construct carrying an Ala285Val mutation that is critical for the formation of a GPI anchor failed to be expressed in transfected C-33A cells. Analysis of the gene structure revealed that the first of the three exons was at least 236 bp longer than previously published and that splicing occurred in the coding region of the mRNA from HEL cells and monocytes. When carrying out 5' inverse RACE-PCR we confirmed the existence of 5 ATGs in the 5' untranslated region (5'UTR). By deletion and site-directed mutagenesis of the ATGs, we showed that the first two ATGs impair translation and that both the 3rd and 5th ATG can be used for translation initiation after expression in C-33A cells. On analysis of the 3'UTR, which contains 2 adenylate/uridylate-rich elements (AREs), we detected one variant in monocytes that would be devoid of a GPI-anchor signal and thus could represent a secreted form of ART4. Thus, alternative splicing and the use of regulatory elements in the 5'UTR and 3'UTR represent means to control ART4 expression.
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PMID:Analysis of mono-ADP-ribosyltransferase 4 gene expression in human monocytes: splicing pattern and potential regulatory elements. 1614 Apr 4

ADP-ribosyltransferases (ARTs) are a family of enzymes that catalyze the covalent transfer of an ADP-ribose moiety, derived from NAD, to an amino acid of an acceptor protein, thereby altering its function. To date, little information is available on the protein target specificity of different ART family members. ART2 is a T-cell-specific transferase, attached to the cell surface by a glycosylphosphatidylinositol (GPI) anchor, and also found in serum. Here we investigated the role of ART2 localization in serum or on the cell surface, or solubilized with detergents or enzymes, on its target protein specificity. We found that detergent solubilization of cell membranes, or release of ART2 by phosphoinositide-specific phospholipase C treatment, altered the ability of ART2 to ADP-ribosylate high or low molecular weight histone proteins. Similarly, soluble recombinant ART2 (lacking the GPI anchor) showed a different histone specificity than did cell-bound ART2. When soluble ART2 was incubated with serum proteins in the presence of [32P]-labeled NAD, several serum proteins were ADP-ribosylated in a thiol-specific manner. Mass spectrometry of labeled proteins identified albumin and transferrin as ADP-ribosylated proteins in serum. Collectively, these studies reveal that the membrane or solution environment of ART2 plays a pivotal role in determining its substrate specificity.
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PMID:Substrate specificity of soluble and membrane-associated ADP-ribosyltransferase ART2.1. 1645 89

Epithelial cells lining human airways and cells recruited to airways participate in the innate immune response in part by releasing human neutrophil peptides (HNP). Arginine-specific ADP-ribosyltransferases (ART) on the surface of these cells can catalyze the transfer of ADP-ribose from NAD to proteins. We reported that ART1, a mammalian ADP-ribosyltransferase, present in epithelial cells lining the human airway, modified HNP-1, altering its function. ADP-ribosylated HNP-1 was identified in bronchoalveolar lavage fluid (BALF) from patients with asthma, idiopathic pulmonary fibrosis, or a history of smoking (and having two common polymorphic forms of ART1 that differ in activity), but not in normal volunteers or patients with lymphangioleiomyomatosis. Modified HNP-1 was not found in the sputum of cystic fibrosis patients or in leukocyte granules of normal volunteers. The finding of ADP-ribosyl-HNP-1 in BALF but not in leukocyte granules suggests that the modification occurred in the airway. Most of the HNP-1 in the BALF from individuals with a history of smoking was, in fact, mono- or di-ADP-ribosylated. ART1 synthesized in Escherichia coli, glycosylphosphatidylinositol-anchored ART1 released with phosphatidylinositol-specific phospholipase C from transfected NMU cells, or ART1 expressed endogenously on C2C12 myotubes modified arginine 14 on HNP-1 with a secondary site on arginine 24. ADP-ribosylation of HNP-1 by ART1 was substantially greater than that by ART3, ART4, ART5, Pseudomonas aeruginosa exoenzyme S, or cholera toxin A subunit. Mouse ART2, which is an NAD:arginine ADP-ribosyltransferase, was able to modify HNP-1, but to a lesser extent than ART1. Although HNP-1 was not modified to a significant degree by ART5, it inhibited ART5 as well as ART1 activities. Human beta-defensin-1 (HBD1) was a poor transferase substrate. Reduction of the cysteine-rich defensins enhanced their ability to serve as ADP-ribose acceptors. We conclude that ADP-ribosylation of HNP-1 appears to be primarily an activity of ART1 and occurs in inflammatory conditions and disease.
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PMID:ADP-ribosyltransferase-specific modification of human neutrophil peptide-1. 1662 71

The transient receptor potential (TRP) protein superfamily is a diverse group of voltage-independent calcium-permeable cation channels expressed in mammalian cells. These channels have been divided into six subfamilies, and two of them, TRPC and TRPM, have members that are widely expressed and activated by oxidative stress. TRPC3 and TRPC4 are activated by oxidants, which induce Na(+) and Ca(2+) entry into cells through mechanisms that are dependent on phospholipase C. TRPM2 is activated by oxidative stress or TNFalpha, and the mechanism involves production of ADP-ribose, which binds to an ADP-ribose binding cleft in the TRPM2 C-terminus. Treatment of HEK 293T cells expressing TRPM2 with H(2)O(2) resulted in Ca(2+) influx and increased susceptibility to cell death, whereas coexpression of the dominant negative isoform TRPM2-S suppressed H(2)O(2)-induced Ca(2+) influx, the increase in [Ca(2+)](i), and onset of apoptosis. U937-ecoR monocytic cells expressing increased levels of TRPM2 also exhibited significantly increased [Ca(2+)](i) and increased apoptosis after treatment with H(2)O(2) or TNFalpha. A dramatic increase in caspase 8, 9, 3, 7, and PARP cleavage was observed in TRPM2-expressing cells, demonstrating a downstream mechanism through which cell death is mediated. Inhibition of endogenous TRPM2 function through three approaches, depletion of TRPM2 by RNA interference, blockade of the increase in [Ca(2+)](i) through TRPM2 by calcium chelation, or expression of the dominant negative splice variant TRPM2-S protected cell viability. H(2)O(2) and amyloid beta-peptide also induced cell death in primary cultures of rat striatal cells, which endogenously express TRPM2. TRPM7 is activated by reactive oxygen species/nitrogen species, resulting in cation conductance and anoxic neuronal cell death, which is rescued by suppression of TRPM7 expression. TRPM2 and TRPM7 channels are physiologically important in oxidative stress-induced cell death.
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PMID:The role of TRP channels in oxidative stress-induced cell death. 1668 99

Intracellular ADP-ribose is an activator of TRPM2, which is a Ca2+-permeable channel and mediates H2O2-induced cell death, in the TRPM2-expressing rat beta-cell line RIN-5F. We examined the effect of extracellular-added ADP-ribose on intracellular Ca2+ concentration in RIN-5F cells. ADP-ribose induced Ca2+ release from the thapsigargin-sensitive Ca2+ store, but not Ca2+ entry across the plasma membrane. A phospholipase C (PLC) inhibitor and a non-specific IP3 receptor inhibitor blocked its Ca2+ release. H2O2-induced Ca2+ entry through TRPM2 was not affected by extracellular ADP-ribose. These findings suggest that extracellular-added ADP-ribose induces Ca2+ release through the PLC-IP3 pathway and does not act as a TRPM2 activator.
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PMID:Extracellular-added ADP-ribose increases intracellular free Ca2+ concentration through Ca2+ release from stores, but not through TRPM2-mediated Ca2+ entry, in rat beta-cell line RIN-5F. 1676 53

Micromolar concentrations of extracellular beta-NAD+ (NAD(e)+) activate human granulocytes (superoxide and NO generation and chemotaxis) by triggering: (i) overproduction of cAMP, (ii) activation of protein kinase A, (iii) stimulation of ADP-ribosyl cyclase and overproduction of cyclic ADP-ribose (cADPR), a universal Ca2+ mobilizer, and (iv) influx of extracellular Ca2+. Here we demonstrate that exposure of granulocytes to millimolar rather than to micromolar NAD(e)+ generates both inositol 1,4,5-trisphosphate (IP3) and cAMP, with a two-step elevation of intracellular calcium levels ([Ca2+]i): a rapid, IP3-mediated Ca2+ release, followed by a sustained influx of extracellular Ca2+ mediated by cADPR. Suramin, an inhibitor of P2Y receptors, abrogated NAD(e)+-induced intracellular increases of IP3, cAMP, cADPR, and [Ca2+]i, suggesting a role for a P2Y receptor coupled to both phospholipase C and adenylyl cyclase. The P2Y(11) receptor is the only known member of the P2Y receptor subfamily coupled to both phospholipase C and adenylyl cyclase. Therefore, we performed experiments on hP2Y(11)-transfected 1321N1 astrocytoma cells: micromolar NAD(e)+ promoted a two-step elevation of the [Ca2+]i due to the enhanced intracellular production of IP3, cAMP, and cADPR in 1321N1-hP2Y(11) but not in untransfected 1321N1 cells. In human granulocytes NF157, a selective and potent inhibitor of P2Y(11), and the down-regulation of P2Y(11) expression by short interference RNA prevented NAD(e)+-induced intracellular increases of [Ca2+]i and chemotaxis. These results demonstrate that beta-NAD(e)+ is an agonist of the P2Y(11) purinoceptor and that P2Y(11) is the endogenous receptor in granulocytes mediating the sustained [Ca2+]i increase responsible for their functional activation.
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PMID:Extracellular NAD+ is an agonist of the human P2Y11 purinergic receptor in human granulocytes. 1692 52


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