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)

Guanine nucleotide binding proteins (G proteins) are regulatory molecules that couple membrane receptors to effector systems such as adenylate cyclase and phospholipase C. The alpha subunits of G proteins bind to guanosine 5'-diphosphate (GDP) in the unstimulated state and guanosine 5' triphosphate (GTP) in the active state. Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide), a specific inhibitor of inosine monophosphate (IMP) dehydrogenase, decreases guanylate synthesis from IMP in HL-60 promyelocytic leukemia cells and depletes intracellular guanine nucleotide pools. This study demonstrates that treatment of HL-60 cells with tiazofurin is associated with a fourfold increase in membrane binding sites for the nonhydrolyzable analogue GDP beta S. This increase in binding sites was associated with a 3.2-fold decrease in GDP beta S binding affinity. Similar findings were obtained with GTP gamma S. These effects of tiazofurin treatment on guanine nucleotide binding were also associated with decreased adenosine diphosphate-ribosylation of specific G protein substrates by cholera and pertussis toxin. The results further demonstrate that tiazofurin treatment results in inhibition of G protein-mediated transmembrane signaling mechanisms. In this regard, stimulation of adenylate cyclase by prostaglandin E2 was inhibited by over 50% in tiazofurin-treated cells. Furthermore, tiazofurin treatment resulted in inhibition of N-formylmethionylleucylphenylalanine-induced stimulation of phospholipase C. Taken together, these results indicate that tiazofurin acts at least in part by inhibiting the ability of G proteins to function as transducers of intracellular signals.
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PMID:Effects of tiazofurin on guanine nucleotide binding regulatory proteins in HL-60 cells. 196 38

G proteins are membrane-bound molecules involved in coupling of surface receptors with signal transduction effector systems in multiple cell types including T lymphocytes. Given that mature T cells which lack antigen receptors (CDl-Ti) are refractory to stimulation through CD2 or other accessory molecules, T cell receptor components likely play a critical role in coupling surface receptors with signal transduction effectors. It has recently been proposed that modulation of T cell receptor components with MAbs results in a physical loss or functional inactivation of G protein(s). In view of the importance of the T cell activation process, we herein examined G proteins in untreated or antibody-modulated Jurkat T cells as well as in genetic variants lacking either CD3-Ti or CD2 surface receptors. 43- and 41-kDa G protein alpha chains are ADP ribosylated with cholera (CTX) and pertussis (PTX) toxins, respectively, in wild type and receptor minus cell populations. In the wild type Jurkat cell line as well as in CD3- and CD2- variants, AlF4- can activate the G protein(s) presumably associated with phospholipase C to generate polyphosphoinositide turnover as well as an increase in cytoplasmic free calcium ions. Furthermore, G protein(s) linked to adenylylcyclase, a pathway which inhibits T lymphocyte activation, can be directly activated with CTX in the absence of CD3-Ti or CD2 on the membrane. Importantly, AlF4- can also induce polyphosphoinositide turnover in Jurkat cells whose T cell receptor proteins have been modulated with anti-CD3 MAb. These data provide functional and biochemical evidence that at least certain G proteins are intact in the absence of surface expression of CD3-Ti or CD2 molecules and imply that CD3-Ti desensitization is not singularly due to G protein loss.
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PMID:Characterization of functional GTP binding proteins in Jurkat T cell mutants lacking either CD3-Ti or CD2 surface receptors. 197 60

Calcium (Ca2+) ion concentrations that are achieved intracellularly upon membrane depolarization or activation of phospholipase C stimulate adenylate cyclase via calmodulin (CaM) in brain tissue. In the present study, this range of Ca2+ concentrations produced unanticipated inhibitory effects on the plasma membrane adenylate cyclase activity of GH3 cells. Ca2+ concentrations ranging from 0.1 to 0.8 microM exerted an increasing inhibition on enzyme activity, which reached a plateau (35-45% inhibition) at around 1 microM. This inhibitory effect was highly cooperative for Ca2+ ions, but was neither enhanced nor dependent upon the addition of CaM (1 microM) to EGTA-washed membranes. The inhibition was greatly enhanced upon stimulation of the enzyme by vasoactive intestinal peptide (VIP) and/or GTP. Prior exposure of cultured cells to pertussis toxin did not affect the inhibition of plasma membrane adenylate cyclase activity by Ca2+, although in these membranes, hormonal (somatostatin) inhibition was significantly attenuated. Maximally effective concentrations of Ca2+ and somatostatin produced additive inhibitory effects on adenylate cyclase. The addition of phosphodiesterase inhibitors demonstrated that inhibitory effects of Ca2+ were not mediated by Ca2(+)-dependent stimulation of a phosphodiesterase activity. These observations provide a mechanism for the feedback inhibition by elevated intracellular Ca2+ levels on cAMP-facilitated Ca2+ entry into GH3 cells, as well as inhibitory crosstalk between Ca2(+)-mobilizing signals and adenylate cyclase activity.
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PMID:Potent and cooperative feedback inhibition of adenylate cyclase activity by calcium in pituitary-derived GH3 cells. 197 2

We have reported the presence of dopamine-1 (DA-1) and dopamine-2 (DA-2) receptors in renal brush border and basolateral membranes. DA-1 agonists stimulate adenylate cyclase (AC) and phospholipase C (PLC) activity in both membranes. Moreover, the ability of a DA-1 agonist (fenoldopam) to stimulate PLC activity is independent of AC activity. A DA-2 agonist (LY171555) by itself was without effect and did not enhance the ability of the DA-1 agonist to stimulate PLC activity. The DA-1 but not DA-2 agonists inhibit Na+/H+ exchange activity in brush border membrane vesicles (BBMV) and Na+/K(+)-ATPase activity in basolateral membranes. However, cAMP inhibits, while protein kinase C (presumably via PLC activity) stimulates, Na+/H+ exchange activity. We therefore determined the effect of DA-1 agonists on Na+/H+ exchange activity when PLC or AC activity was blocked using neomycin or dideoxyadenosine, respectively. The drugs were incubated with minced renal cortex prior to preparation of BBMV by differential centrifugation and MnCl2 precipitation. Enrichment of BBMV was not affected by drug treatment. The Na+/H+ exchange activity was assessed by measuring amiloride (1 mmol/L) sensitive 22Na+ uptake in BBMV (pHi = 5.5, pHo = 7.5, Nai+ = O, Nao+ = 1 mmol/L). Neomycin inhibited DA and DA-1-stimulated PLC activity in BBMV in a concentration dependent manner (10(-6) to 10(-4) mol/L). Neomycin (10(-4) mol/L) completely blocked the ability of DA and DA-1 agonist to stimulate PLC activity but had no consistent effect on DA-1 inhibited Na+/H+ exchange activity. Dideoxyadenosine inhibited DA and DA-1 simulated AC activity without affecting DA-1 stimulated PLC activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The signal transducer for the dopamine-1 regulated sodium transport in renal cortical brush border membrane vesicles. 197 43

The potential for cross-talk between the adenyl cyclase and phosphoinositide (PPI) lipid second messenger system was investigated in astrocytes cultured from neonatal rat brain. Glutamate-stimulated PPI turnover, measured by the formation of total inositol phosphates from myo-[3H]inositol-labeled lipids, was inhibited in a concentration-dependent manner by the elevation of intracellular cyclic AMP levels produced either by stimulation of the isoproterenol receptor linked to adenyl cyclase or by its direct activation by forskolin. N6,2'-O-Dibutyryl cyclic AMP, an analogue that can also activate cyclic AMP-dependent kinase, inhibited glutamate-stimulated PPI turnover in a concentration-dependent manner as well, a result suggesting that cyclic AMP-dependent kinase is involved in mediating the inhibition. Inclusion of an inhibitor of cyclic AMP-dependent kinase, 1-(5-isoquinolinesulfonyl)-2 methylpiperazine dihydrochloride or N-(2-guanidinoethyl)-5-isoquinolinesulfonamide hydrochloride, blocked the cyclic AMP-mediated inhibition in a concentration-dependent manner, a finding further supporting this hypothesis. The site of inhibition of the phosphoinositol lipid pathway by cyclic AMP was probed using a digitonin-permeabilized cell system. Guanosine 5'-O-(3-thiotriphosphate), a nonhydrolyzable analogue of GTP, stimulated PPI turnover and potentiated glutamate-stimulated PPI turnover, and guanosine 5'-O-(3-thiodiphosphate) inhibited glutamate-stimulated PPI turnover in these cells, results providing evidence that glutamate receptors are coupled to phospholipase C by a guanine nucleotide binding protein in astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glutamate-stimulated, guanine nucleotide-mediated phosphoinositide turnover in astrocytes is inhibited by cyclic AMP. 197 58

Results obtained with the use of nonpeptide angiotensin II receptor antagonists have suggested the presence of multiple subtypes of angiotensin II receptors in rat adrenal gland. However, the effects of nonpeptide antagonists on second messenger production by angiotensin II have not been investigated. In rat liver, angiotensin II can both activate phospholipase C, generating inositol polyphosphates and raising internal calcium, and inhibit adenylate cyclase. DuP 753 and PD123177, two nonpeptide angiotensin II antagonists, were used to characterize the receptor population in rat liver and to investigate the possibility that different angiotensin II receptor subtypes couple to different second messenger pathways. DuP 753 could completely antagonize the binding of angiotensin II in rat liver membranes, with a K1 of 9.3 x 10(-9) M. PD123177 had no effect on the binding of angiotensin II in rat liver at concentrations between 1 x 10(-9) M and 3 x 10(-5) M, in contrast to its ability to inhibit angiotensin II binding in rat adrenal. At a concentration of 10(-5) M, DuP 753 could inhibit increases in internal free calcium, could prevent production of inositol polyphosphates, and could attenuate inhibition of adenylate cyclase produced by angiotensin II. PD123177 at concentrations between 1 x 10(-9) M and 3 x 10(-5) M was ineffective in all of these assays. The results indicate that DuP 753 can displace the binding of angiotensin II at all receptor sites in rat liver and that this drug can attenuate both of the second messenger events produced by the angiotensin II receptor.
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PMID:DuP 753 can antagonize the effects of angiotensin II in rat liver. 201 58

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 possibility that arachidonic acid (AA) plays a role in the regulation of steroidogenesis in goldfish was investigated using preovulatory ovarian follicles incubated in vitro. AA was shown to act in a time- and dose-dependent manner to stimulate testosterone production. AA in the range of 10(-5) to 10(-4) M increased testosterone production within 2 hr and had a maximal effect by 9 hr. The magnitude of the testosterone response to AA was similar to that observed when ovarian follicles were incubated with human chorionic gonadotropin (hCG). Ovarian follicles incubated with AA and either hCG or forskolin (adenylate cyclase activator) produced more testosterone than follicles incubated with either of these compounds alone. The actions of AA on testosterone production were completely blocked by cyclooxygenase inhibitors (indomethacin or ibuprofen) and were reduced by 50% by the lipoxygenase inhibitor nordihydroguaiaretic acid. Phospholipase C was far more effective than phospholipase A2 in the stimulation of testosterone production. Taken together, these results suggest that AA formed subsequent to the action of phospholipase C on membrane phospholipids has a role in the regulation of steroidogenesis in preovulatory goldfish ovarian follicles.
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PMID:Arachidonic acid stimulates steroidogenesis in goldfish preovulatory ovarian follicles. 210 68

Several classes of growth factors can be distinguished that act through different signal transduction pathways. One class is constituted by the peptide growth factors that bind to receptors with ligand-dependent protein tyrosine kinase activity. Another class of mitogens activates a phosphoinositide-specific phospholipase C via a receptor-linked G protein. An intriguing member of this class is lysophosphatidic acid (LPA). LPA mitogenicity is not dependent on other mitogens and is blocked by pertussis toxin. LPA evokes at least three separate signalling cascades: (i) activation of a pertussis toxin-insensitive G protein mediating phosphoinositide hydrolysis; (ii) release of arachidonic acid in a GTP-dependent manner, but independent of prior phosphoinositide hydrolysis; and (iii) activation of a pertussis toxin-sensitive Gi protein mediating inhibition of adenylate cyclase. The peptide bradykinin mimics LPA in inducing responses (i) and (ii), but fails to activate Gi and to stimulate DNA synthesis. Our results suggest that the mitogenic action of LPA occurs through Gi or a related pertussis toxin substrate and that, unexpectedly, the phosphoinositide hydrolysis pathway is neither required nor sufficient, by itself, for mitogenesis.
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PMID:Growth factor-like action of lysophosphatidic acid: mitogenic signalling mediated by G proteins. 211 27

The present work examines lateral mobility of the vasopressin V1-type receptor, representing the first determination of lateral mobility of a hormone receptor coupled to phospholipase C activation. The V1-receptor of A7r5 smooth muscle cells was characterized for [Arg8] vasopressin (AVP) binding properties and affinity for the fluorescent vasopressin analogue 1-deamino[8-lysine (N6-tetramethylrhodamylaminothiocarbonyl)] vasopressin (TR-LVP). TR-LVP was biologically active in A7r5 cells, inducing inositol 1,4,5-trisphosphate turnover in similar fashion to AVP. TR-LVP was used to specifically label the V1-receptor of living A7r5 cells, and lateral mobility of the V1-receptor was measured using the technique of fluorescence microphotolysis. The apparent lateral diffusion coefficient (D) at 37 degrees C was 5.1 x 10(-10) cm2/s, falling to 2.9 x 10(-10) cm2/s at 13 degrees C. These D values are higher than comparable values for the adenylate cyclase-activating vasopressin V2-receptor of LLC-PK1 renal epithelial cells analysed with the same fluorescent ligand. In contrast to the V2-receptor, no marked temperature dependence was observed for the V1-receptor mobile fraction (f). From 37 degrees C to 13 degrees C, f was relatively low (between 0.4 and 0.5) consistent with V1-receptor immobilization through internalization, which is rapid even at room temperature in A7r5 cells. These differences between V1- and V2-receptor lateral mobility are discussed in terms of the implications for their respective signal transduction systems.
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PMID:Lateral mobility of the phospholipase C-activating vasopressin V1-type receptor in A7r5 smooth muscle cells: a comparison with the adenylate cyclase-coupled V2-receptor. 214 82


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