Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypothesis that disparate neutrophil functional responses to various chemoattractants are regulated by receptor-specific rates of G protein activation was examined in HL-60 granulocytes. The initial rates of G protein activation and the affinity of receptor-stimulated G proteins for GTP gamma S in HL-60 membranes stimulated by fMet-Leu-Phe, C5a, and leukotriene B4 (LTB4) differed significantly among the chemoattractants, with a rank order of fMet-Leu-Phe > C5a > LTB4. Equilibrium GTP gamma S binding showed that all three chemoattractants activated a common pool of G proteins. Stimulation of phospholipase D activation, measured as phosphatidylethanol generation, and superoxide release in intact cells also occurred with a rank order of fMet-Leu-Phe > C5a > LTB4. On the other hand, the rank order of receptor affinities for ligand and of the EC50 of chemoattractant stimulation of GTP gamma S binding was C5a > LTB4 > fMet-Leu-Phe. C5a and LTB4 receptor densities were similar but were less than formyl peptide receptor density. Graded pertussis toxin treatment proportionally reduced superoxide release and phospholipase D activation to all three chemoattractants. The results suggest that receptor-specific differences in G protein affinity for guanine nucleotides lead to different rates of guanine nucleotide exchange and, thereby, contribute to disparate effector enzyme and functional responses.
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PMID:Chemoattractant receptor-specific differences in G protein activation rates regulate effector enzyme and functional responses. 772 25

We have characterized a membrane-bound phosphatidylcholine (PC) specific phospholipase C (PC-PLC) in plasma membranes from rat cardiac muscle, and have investigated the role of PC-PLC and PC-specific phospholipase D (PC-PLD) activities in the mechanism of action of atrial natriuretic factor (ANF). In purified sarcolemma, ANF stimulated over a wide range of concentrations with a maximum at 10(-11) M the hydrolysis of phosphatidylcholine through PC-PLD giving phosphatidate and choline, whereas higher concentrations of ANF (10(-10) M) preferentially stimulated PC breakdown through PC-PLC to form diacylglycerol and phosphocholine. To confirm the involvement of the PC-PLD in the mechanism of ANF action, we measured the transphosphatidylation reaction, a specific assay for this phospholipase which in the presence of ethanol catalyses the phosphatidylethanol formation from PC. ANF stimulated phosphatidylethanol formation with the same dose-response behavior as phosphatidate formation. The significant diacylglycerol increase at 10(-10) M ANF, in the presence of propranolol, a potent inhibitor of phosphatidate phosphatase which can hydrolyse phosphatidate to give diacylglycerol, suggested a direct involvement of PC-PLC. The use of GTP-gamma-S, a non hydrolysable analog of GTP, and of pertussis toxin showed the involvement of a pertussis toxin insensitive G protein in PC-PLC mediated ANF signal transduction. We suggest a differential effect of ANF on PC breakdown by phospholipases C and D depending on the concentration of the peptide.
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PMID:Selective activation by atrial natriuretic factor of phosphatidylcholine-specific phospholipase activities in purified heart muscle plasma membranes. 773 Oct 62

Since adenosine A1 receptors activate phospholipase C (PLC) in DDT1 MF-2 smooth muscle cells we have examined whether phospholipase D (PLD) and protein kinase C (PKC) activities are also increased. The formation of diacylglycerol was also measured. PKC activity was determined by measuring the phosphorylation of two peptide substrates after rapidly permeabilizing the cells. PLD activity was determined by measuring the formation of phosphatidylethanol. N6-cyclopentyladenosine, a selective adenosine A1 receptor agonist (100 nM) and bradykinin (1 microM) both stimulated the formation of diacylglycerol. The activation was biphasic with a rapid, transient increase (within 1 min) followed by a second increase. N6-cyclopentyladenosine increased the activity of PKC (EC50 5.6 nM) and PLD (EC50 18.7 nM). This was blocked by treatment of cells with pertussis toxin or the adenosine A1 receptor selective antagonist, 8-cyclopentyl-1,3-dipropylxanthine. Ki values (3 nM for PKC; 0.1 nM for PLD) were consistent with responses mediated via adenosine A1 receptors. Bradykinin (1 microM) also increased PKC and PLD activity, but these responses were insensitive to pertussis toxin treatment. The activation of PKC by N6-cyclopentyladenosine or bradykinin was transient, reaching a maximum at 1-2 min, and was preceded by increases in the formation of diacylglycerol. When adenosine A1 and bradykinin receptors were activated simultaneously, a synergistic activation of PKC was seen. There was no synergistic effect on PLD activity. In summary, the present study shows that activation of adenosine receptors of the A1 subtype increases PKC and PLD activity. Simultaneous activation of adenosine A1 and bradykinin receptors causes a synergistic increase in PKC.
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PMID:Activation of adenosine A1 and bradykinin receptors increases protein kinase C and phospholipase D activity in smooth muscle cells. 777 Jan

The activation of phospholipase D (PLD) induced by formyl peptides (fMLP), as evaluated by production of tritiated phosphatidylethanol (PEt) and phosphatidic acid (PA) in polymorphonuclear leukocytes (PMN), was markedly enhanced (50-125%) by low okadaic acid concentrations (0.25-0.5 microM) but inhibited by higher concentrations (2-3 microM), although the drug caused protein hyperphosphorylation. Both effects of okadaic acid were amplified when PLD activation was primed with cytochalasin B. Stimulation of PMN with mastoparan, a wasp venom toxin that activates Pertussis toxin(PTX)-sensitive G proteins, resulted in a weak calcium-dependent production of PEt which was respectively enhanced and inhibited by okadaic acid (1-2 microM) in unprimed and cytochalasin-primed PMN. The results show that low okadaic acid concentrations primed fMLP-mediated activation of PLD, in keeping with a down-regulatory role of protein phosphatases. The contrasting effects of okadaic acid in mastoparan-stimulated PMN further suggest that protein phosphatases may regulate the generation of second messengers through alteration of major signaling events at/or downstream of PTX-sensitive G proteins (Gi).
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PMID:Okadaic acid, an inhibitor of type 1 and type 2A phosphatases, modulates the activation of phospholipase D in formyl peptide- and mastoparan-stimulated human neutrophils. 780 84

Interleukin-8 (IL-8) and the structurally related cytokines neutrophil-activating peptide-2 (NAP-2) and GRO alpha are powerful chemotactic agents for human neutrophils. Although these three chemokines act by binding to overlapping but not identical receptor subsets, the data available to date have stressed the similarities in their mechanisms of action. The present studies were undertaken to further our understanding of the signal transduction mechanisms associated with these neutrophil agonists. IL-8, NAP-2, and GRO alpha stimulated similar increases in the level of cytoplasmic free calcium. They were also shown to stimulate qualitatively similar increases in the levels of protein tyrosine phosphorylation. In contrast, only IL-8 enhanced the formation of phosphatidylethanol (PEt), the product catalyzed by phospholipase D (PLD) in the presence of ethanol. The formation of PEt stimulated by IL-8 was inhibited by pertussis toxin and the tyrosine kinase inhibitors erbstatin and herbimycin A. The ability of IL-8 to stimulate the activity of PLD was additively enhanced, or primed, by cytochalasin B and by tumor necrosis factor alpha. Although all three chemokines increased the level of free cytoplasmic calcium to the same extent, IL-8 was significantly more potent than either NAP-2 or GRO alpha with respect to its ability to enhance CD11b expression and to stimulate chemotactic and oxidative responses. The differences between IL-8, NAP-2, and GRO alpha in their ability to stimulate PLD is likely to be related to their respective binding affinities for the two IL-8 receptors (IL-8R-A and IL-8R-B). These results suggest that the signalling pathways activated by IL-8R-A and IL-8R-B diverge at a step preceding the activation of PLD.
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PMID:Diverging signal transduction pathways activated by interleukin-8 and related chemokines in human neutrophils: interleukin-8, but not NAP-2 or GRO alpha, stimulates phospholipase D activity. 781 7

Pertussis toxin was used to block insulin-stimulated phosphatidylinositol (PI)-glycan hydrolysis, consequent de novo synthesis of phosphatidic acid (PA) and the diacylglycerol (DAG) production that results from these two related processes in BC3H-1 myocytes. In contrast, pertussis toxin pretreatment did not inhibit insulin-stimulated hydrolysis of phosphatidylcholine (PC) which was found to be at least partly due to activation of a phospholipase D. Moreover, pertussis toxin-insensitive PC hydrolysis was accompanied by rapid biphasic increases in DAG and translocative activation of protein kinase C (PKC). Insulin-stimulated glucose transport was also insensitive to pertussis toxin pretreatment. Our findings suggest that insulin-stimulated PC hydrolysis pays an important role in DAG/PKC signalling during insulin action.
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PMID:Insulin-stimulated phosphatidylcholine hydrolysis, diacylglycerol/protein kinase C signalling, and hexose transport in pertussis toxin-treated BC3H-1 myocytes. 785 72

We examined the effect of endothelin-1 (ET-1) on phosphatidylcholine-hydrolyzing phospholipase D activity in osteoblast-like MC3T3-E1 cells. ET-1 stimulated the formation of choline (EC50 10 nM) as well as that of inositol phosphates (EC50 1.2 nM). The effects of ET-1 and 12-O-tetradecanoylphorbol-13-acetate, a protein kinase C-activating phorbol ester, were additive. Staurosporine enhanced the ET-1-induced formation of choline. NaF or pertussis toxin were ineffective. The results indicate that ET-1 activates phospholipase D independent of protein kinase C in osteoblast-like cells.
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PMID:Effect of endothelin-1 on phospholipase D activity in osteoblast-like cells. 785 25

TNF-alpha enhances the response of polymorphonuclear leukocytes (PMN) to chemoattractants: however, the mechanism by which this occurs is unclear. We addressed the hypothesis that TNF-alpha enhances the PMN response to chemoattractants by increasing chemoattractant receptor transmembrane signaling, using fMLP as the model chemoattractant. fMLP-stimulated guanine nucleotide binding (G) protein activation was significantly increased in plasma membranes isolated from PMNs exposed to TNF-alpha 100 U/ml for 10 minutes (TNF-M), compared to membranes from control cells (CM). Formyl peptide receptor number and affinity were not significantly different in CM and TNF-M. Gi and Gs content were increased in TNF-M as measured by pertussis toxin and cholera toxin (CT) catalyzed ADP-ribosylation, respectively. The increased Gi was coupled to the formyl peptide receptor as shown by receptor-specific CT labeling of Gi. Immunoblot analysis showed that both G alpha i2 and G alpha 3 were increased in TNF-M. The functional activity of the increased G protein content was demonstrated by increased NaF-stimulated phospholipase D activity in TNF-alpha-treated PMNs. We conclude that TNF-alpha rapidly stimulates increased PMN plasma membrane expression of G proteins that couple formyl peptide receptors to effector enzymes. Regulation of G protein expression may be a significant mechanism by which TNF regulates PMN function.
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PMID:TNF-alpha stimulates increased plasma membrane guanine nucleotide binding protein activity in polymorphonuclear leukocytes. 788 23

Substance P (SP) is a tachykinin involved in the regulation of inflammatory processes. Tachykinins bind to three subtypes of neurokinin (NK) receptors. However, recently we demonstrated that monocytes express a SP binding site that is not one of the known NK receptors. Activation of this SP receptor leads to the stimulation of MAP kinase in monocytes. In the present paper we show that this novel SP binding site is coupled to a GTP binding protein of the Gi alpha 1/2 subclass. Triggering of the SP receptor leads to a rapid rise in cytosolic calcium. In a more sustained way, SP stimulates phospholipase D (PLD) activity in human monocytes. The effects of SP on calcium, PLD, and MAP kinase activity can be blocked by pretreatment of the cells with pertussis toxin, which is in agreement with receptor coupling to Gi. At a functional level, stimulation of the non-NK SP receptor on monocytes results in the induction of IL-6 production. We show here that the order of potency for activation of monocytes by various ligands is directly related to the Ki for displacement of labeled SP by these ligands. Therefore, our data strongly suggest that the effects of SP are mediated via the novel SP receptor we recently described.
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PMID:Activation of human monocytes via a non-neurokinin substance P receptor that is coupled to Gi protein, calcium, phospholipase D, MAP kinase, and IL-6 production. 793 May 88

Incubation of IIC9 fibroblasts with lysophosphatidic acid (LPA) induced an increase in the amount of filamentous actin (F-actin), which was concentration-dependent with a maximal effect at 100 ng/ml. Phosphatidic acid (PA) also produced a concentration-dependent increase of F-actin, but it was less potent than LPA. The LPA-induced increase in F-actin was rapid and sustained for at least 60 min. LPA rapidly increased the levels of PA and choline, with maximal increases at 5 min and 30 s respectively. LPA also caused a monophasic increase in diacylglycerol (DAG) which lagged behind the increases in PA and choline. LPA stimulated phosphatidylbutanol formation in the presence of butanol and produced a small increase in inositol phosphates that was much less than that induced by alpha-thrombin. Pretreatment of cells with pertussis toxin (PTX) caused greater than 50% inhibition of the LPA-stimulated increases in PA, DAG and choline. PTX increased the LPA concentration required to induce half-maximal actin polymerization by about 10-fold. PTX caused a similar shift in the dose-response curve for LPA-induced PA formation. These results suggest that LPA induces an increase in PA by activating a phosphatidylcholine-hydrolysing phospholipase D via a PTX-sensitive G-protein and that the increase in PA is involved in the activation of actin polymerization.
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PMID:Lysophosphatidic acid activation of phosphatidylcholine-hydrolysing phospholipase D and actin polymerization by a pertussis toxin-sensitive mechanism. 794 65


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