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: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of SH-SY5Y neural cells with mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (the key enzyme in purine nucleotide biosynthesis), reduced the cellular content of GTP by 94% relative to its concentration in control cells (43 nmol/mg protein) without altering the level of GDP. Although in GTP-depleted intact cells the receptor binding parameters (Kd and Bmax) of the opioid antagonist [3H]naltrexone were unchanged from those in untreated cells, the binding affinity of the mu-selective opioid agonist [3H]Tyr-D-Ala-Gly-(Me)- Phe-Gly-ol ([3H]DAMGO) was enhanced 2-fold. Furthermore, the kinetics of ligand/receptor interaction revealed that in the nucleotide-depleted cells, the dissociation rate constant for [3H]DAMGO was reduced by 44%. Initial exposure of SH-SY5Y cells to pertussis toxin reduced high-affinity ligand binding by 95% and abolished the effect of MPA treatment. Renewed incubation of the GTP-depleted cells with guanosine restored the original GTP levels and agonist binding. Neither MPA nor guanosine treatment changed the Bmax of [3H]DAMGO binding. Forskolin- and prostaglandin E1-stimulated adenylyl cyclase activities were decreased significantly in GTP-depleted cells. DAMGO and [D-Pen2,D-Pen5]enkephalin inhibitions of adenylyl cyclase were also affected with MPA treatment. Maximal inhibition of forskolin-stimulated adenylyl cyclase activity by both of the agonists was reduced, whereas MPA caused a 2-fold reduction in potency for DAMGO. The results show that reduction in endogenous GTP levels leads to noticeable changes in agonist, receptor, and G protein interactions, as measured by agonist binding, and to subsequent diminution of the signal transduction, as reflected by the cAMP levels.
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PMID:Reversible modulation of opioid receptor binding in intact neural cells by endogenous guanosine triphosphate. 747 95

Apoptosis of natural killer (NK) cells can be induced by non-specific physical damage (UV irradiation, heat shock) or by simultaneous ligation of the CD16 and the interleukin-2 receptor (IL-2R) molecules, but not with either anti-CD16 or IL-2 alone. Whereas blockade of GTP-binding protein (G protein)-mediated signal transduction using ADP-ribosylating bacterial toxins or the GTPase-resistant GTP analog guanosine 5'-0-(3-thiotriphosphate (GTP gamma S) does not affect non-specific induction of NK cell apoptosis, such interventions do inhibit induction of apoptosis by anti-CD16/IL-2. The G proteins involved in the regulation of activation-induced NK apoptosis are sensitive to pertussis toxin (PTX) and to the non-specific GTP analog GTP gamma S but not to cholera toxin, Pseudomonas exotoxin A or diphtheria toxin. A pertussis toxin mutant that lacks ADP-ribosylating activity, but conserves the membrane translocating and T cell-mitogenic effects of the native molecule, fails to inhibit NK apoptosis. To exert their apoptosis-inhibitory effect, PTX and GTP gamma S must be employed before cells are activated. Later addition has no effect, suggesting the implication of G proteins in the transmission of apoptosis-inducing signals, but not in the effector stage of apoptosis. Pre-incubation with PTX or GTP gamma S does not affect the activation of NK cells by CD16 cross-linking, IL-2 stimulation- or both, as assessed by the induction of CD69 expression, protein tyrosine phosphorylation and calcium mobilization. Moreover, neither PTX nor GTP gamma S compromise the effector function of NK cells or the susceptibility of target cells to NK-mediated lysis. These data suggest apoptosis as a novel mechanism by which NK responses may be controlled in vivo, as well as an experimental and therapeutical strategy to counteract endogenous down-regulation of NK responses.
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PMID:Pertussis toxin-sensitive GTP-binding proteins regulate activation-induced apoptotic cell death of human natural killer cells. 748 48

Monoclonal antibodies to the alpha L beta 2 integrin inhibit the binding of type I collagen to PMN (polymorphonuclear neutrophil leukocytes) as well as the subsequent stimulation of superoxide production and enzyme secretion-elicited by this collagen. Pepsinized collagen still binds PMN but no longer stimulates them. The I domain of the alpha chain of the integrin is involved in the binding. Two sequences of the alpha 1(I) polypeptide chain of collagen participate in the process. Experiments of competitive inhibition by synthetic peptides showed that the sequence RGD (915-917) is used for binding to the cells and DGGRYY (1034-1039) serves to stimulate PMN. Experiments of radioactive labeling of the cells and affinity chromatography on Sepharose-collagen confirmed the presence in PMN extracts of two proteins, 95 and 185 kDa, respectively, corresponding to the molecular weights of the beta 2 and alpha L chains of the integrin and recognized by their specific monoclonal antibodies. The transduction pathways depending on the alpha L beta 2 integrin do not involve a G protein (ruled out by the use of cholera and pertussis toxins), whereas the cytoskeleton was found to participate in the process, as evidenced by inhibition by cytochalasin B. After collagen stimulation, cytoplasmic inositol trisphosphate and calcium ion increased sharply for less than 2 min. The use of the inhibitors staurosporine and calphostin C demonstrated that protein kinase C was involved. Evaluation of the activity of this enzyme showed that, upon stimulation of PMN with collagen I, it was translocated to plasma membrane. Acrylamide gel electrophoresis of the protein bands corresponding to the integrin alpha L beta 2, followed by immunoblotting using monoclonal antibodies to phosphotyrosine, permitted us to demonstrate that, prior to stimulation by type I collagen, there was no phosphorylation, whereas after stimulation, both alpha L and beta 2 chains were stained by anti-phosphotyrosine antibodies. The adhesion of PMN to pepsinized type I collagen triggered tyrosine phosphorylation of the beta 2 chain of the integrin, without stimulating O2-. production by these cells, whereas their stimulation by complete type I collagen induced the tyrosine phosphorylation of both alpha L and beta 2 subunits. The tyrosine phosphorylation of both integrin subunits during transduction of stimuli is a heretofore undescribed phenomenon that may correspond to a new system of transmembrane communication.
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PMID:The binding of type I collagen to lymphocyte function-associated antigen (LFA) 1 integrin triggers the respiratory burst of human polymorphonuclear neutrophils. Role of calcium signaling and tyrosine phosphorylation of LFA 1. 749 7

Binding of FMLP to the neutrophil N-formyl peptide receptor (FPR) transmits signals through pertussis toxin-sensitive G proteins triggering Ca2+ flux, superoxide production, granule exocytosis, and neutrophil aggregation and adhesion involving the beta 2 (CD18) integrins. Expression of the FPR in mouse fibroblasts or human kidney cells has been shown to confer an N-formyl peptide-inducible Ca2+ flux in transfectants. Here we demonstrate that the transfected receptor can also support ligand-induced alterations in cellular adhesion. We established stable transfectants of mouse L1-2 pre-B cells with cDNA for human FPR (L1-2 FPR cells). The transfectants bind N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein with 1.4 x 10(5) sites per cell and a dissociation constant of 3.3 nM. Stimulation with FMLP induces a transient Ca2+ flux. FMLP also triggers adhesion of L1-2 FPR cells to TNF-alpha- or LPS-activated bEnd3 cells (mouse brain-derived endothelial cells) and to purified mouse VCAM-1. Binding is inhibited by Abs to VCAM-1 and to the alpha-chain of its lymphocyte receptor (the alpha 4 beta 1 integrin, VLA-4). Stimulation with FMLP does not induce a change in cell surface expression of alpha 4. Induced adhesion to VCAM-1 is rapid, detectable at the earliest times measurable (30 to 60 s after FMLP addition), and is inhibited by pertussis toxin. We conclude that FPR can mediate integrin activation not only in neutrophils but also in lymphocytes, and can trigger rapid adhesion via lymphocyte alpha 4 beta 1. The adhesion of lymphocytes is critical to their migration and targeting; our results suggest the possibility of manipulating adhesive responses through expression of chemoattractant receptors in lymphoid cells engineered for cellular therapy, allowing targeted adhesion and potentially migration in response to locally administered ligands.
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PMID:Ligand-induced adhesion to activated endothelium and to vascular cell adhesion molecule-1 in lymphocytes transfected with the N-formyl peptide receptor. 751 63

In dibutyryl-cAMP-differentiated HL-60 cells, histamine H1 and formyl peptide receptors mediate increases in the cytosolic Ca2+ concentration ([Ca2+]i) via pertussis toxin-sensitive G proteins of the Gi family. We compared the effects of 2-(3-chlorophenyl)-histamine (CPH) [2-[2-(3-chlorophenyl)-1H-imidazol-4-yl] ethanamine], one of the most potent and selective H1 receptor agonists presently available, with those of histamine and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) in these cells. CPH increased [Ca2+]i through Ca2+ mobilization and Ca2+ influx. Unlike histamine-induced rises in [Ca2+]i, those induced by CPH were not desensitized in a homologous manner, and there was no cross-desensitization between CPH and histamine. Like fMLP, CPH activated phospholipases C and D, tyrosine phosphorylation, superoxide anion formation, and azurophilic granule release. The effects of CPH on [Ca2+]i, phospholipase D, and superoxide anion formation were inhibited by pertussis toxin. CPH and fMLP stimulated high affinity GTP hydrolysis by Gi proteins in HL-60 membranes. They also enhanced binding of guanosine-5'-O-(3-thio)triphosphate and GTP azidoanilide to, and cholera toxin-catalyzed ADP-ribosylation of, Gi protein alpha subunits. Histamine receptor antagonists did not inhibit the stimulatory effects of CPH, and CPH did not reduce fMLP binding in HL-60 membranes. Our data suggest that CPH activates Gi proteins in HL-60 cells through a receptor agonist-like mechanism that is, however, independent of known histamine receptor subtypes and formyl peptide receptors. CPH may be an agonist at an as yet unknown histamine receptor subtype or, by analogy with other cationic-amphiphilic substances, may activate G proteins directly. Future studies will have to take into consideration the fact that CPH, in addition to activating H1 receptors, may show other, most unexpected, stimulatory effects on G protein-mediated signal transduction processes.
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PMID:The H1 receptor agonist 2-(3-chlorophenyl)histamine activates Gi proteins in HL-60 cells through a mechanism that is independent of known histamine receptor subtypes. 751 61

Stimulation of Rat-1 fibroblasts, stably transfected with alpha 2C10 receptors, with the specific alpha 2 agonist UK14304 led to the tyrosine phosphorylation and activation of the p42 and p44 isoforms of MAP kinase. Tyrosine phosphorylation of the MAP kinases was prevented by pertussis toxin. In unstimulated cells, there was constitutive tyrosine phosphorylation and activation of the p44 but not the p42 MAP kinase. This effect was not seen in non-transfected parental Rat-1 fibroblasts.
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PMID:Regulation of p42 and p44 MAP kinase isoforms in Rat-1 fibroblasts stably transfected with alpha 2C10 adrenoreceptors. 751 3

The tyrosine phosphorylation responses initiated in human neutrophils by soluble and particulate agonists were characterized. Chemotactic factors, hematopoietic growth factors, and inflammatory microcrystals stimulated in a time- and concentration-dependent manner the tyrosine phosphorylation of distinct patterns of substrates: pp120, pp85, pp70, and pp60 in the case of chemotactic factors; pp155, pp130, pp120, pp85, pp60, and pp40 in the case of granulocyte macrophage-CSF; and pp130, pp120, pp70, and pp60 in the case of monosodium urate (MSU) crystals. Several of the single bands on one-dimensional blots (including pp40, pp70, and pp120) could be resolved into multiple spots on two-dimensional gels. The responses of several other chemotactic factors resembled those of FMLP. Cytokineplasts retained the capacity to respond to FMLP, granulocyte-macrophage-CSF, or MSU crystals with a stimulation of tyrosine phosphorylation, and contained the major substrates detected in intact neutrophils. Several unrelated tyrosine kinase inhibitors (herbimycin A, genistein, and erbstatin) strongly diminished the tyrosine phosphorylation response to chemotactic factors. Pertussis toxin abrogated the tyrosine phosphorylation response to FMLP, whereas protein kinase C (Ro 21-8220, chelerithryn) inhibitors were without effect. Chelation of intracellular calcium attenuated the tyrosine phosphorylation response to FMLP. These results indicate that G proteins play a crucial role in the coupling of chemotactic factor receptors to tyrosine phosphorylation and that this coupling occurs in parallel to that of phospholipase C. These results also underline the complexity of the transduction pathways implicated in the initiation of tyrosine phosphorylation.
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PMID:Tyrosine phosphorylation in activated human neutrophils. Comparison of the effects of different classes of agonists and identification of the signaling pathways involved. 751 26

Thrombin and the thrombin receptor agonist peptide (TRAP) caused a rise in intracellular calcium concentration ([Ca2+]i) in the human osteoblast-like cell line Saos-2. Striking differences in the [Ca2+]i signals elicited by these agonists were revealed. In cell populations, thrombin induced a transient increase in [Ca2+]i while TRAP caused a biphasic [Ca2+]i response consisting of an initial peak and a sustained plateau phase. In individual cells, thrombin mainly caused a single [Ca2+]i transient while TRAP induced repetitive [Ca2+]i spikes. Neither tyrosine phosphorylation, cAMP-dependent phosphorylation, nor pertussis toxin-sensitive G proteins appeared to be involved in thrombin receptor [Ca2+]i signaling in this cell line. However, the sustained [Ca2+]i response caused by TRAP was converted into a transient, thrombin-like response by pretreatment with serine/threonine phosphatase inhibitors. Pretreatment with the phorbol ester phorbol 12-myristate 13-acetate (PMA) abrogated thrombin receptor [Ca2+]i signaling, and TRAP-induced Ca2+ entry was inhibited by the acute treatment with PMA. In contrast, Ca2+ entry stimulated by thapsigargin was not sensitive to agents affecting serine/threonine phosphorylation. The observation that thrombin and TRAP, despite being agonists for a common receptor, induce dissimilar [Ca2+]i responses indicates that binding of TRAP alone is insufficient to fully regulate the thrombin receptor in Saos-2 cells.
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PMID:Differences in intracellular calcium signaling after activation of the thrombin receptor by thrombin and agonist peptide in osteoblast-like cells. 751 33

The characteristics of protein tyrosine phosphorylation were examined in Rat-1 fibroblasts in response to endothelin-1 (ET-1) and 1-oleoyl-lysophosphatidic acid (LPA). Both agonists stimulated the biphasic tyrosine phosphorylation of at least three major proteins of approx. 120 kDa (pp116, pp120 and pp130) and two of 80 kDa (pp80 and pp70). Immunoprecipitation experiments indicated that the pp120 protein corresponded to the recently described focal adhesion protein kinase pp125fak. Phorbol 12-myristate 13-acetate, alone or in combination with the calcium ionophore A23187, also stimulated the phosphorylation of pp125fak but to a smaller extent than LPA or ET-1. Removal of both extracellular and intracellular Ca2+ did not significantly reduce LPA- and ET-1-stimulated tyrosine phosphorylation of pp125fak. In cells where protein kinase C activity was down-regulated or inhibited, ET-1-stimulated tyrosine phosphorylation of pp125fak was reduced to a greater extent than phosphorylation in response to LPA. In addition, ET-1-stimulated tyrosine phosphorylation of pp80 was decreased by 50-70% in response to protein kinase C inhibition at both 2 and 60 min whereas LPA-stimulated tyrosine phosphorylation of this protein was only reduced at 2 min. Pretreatment with pertussis toxin reduced the tyrosine phosphorylation of pp42 and pp44 forms of mitogen-activated protein kinase in response to both ET-1 and LPA but reduced the tyrosine phosphorylation of pp125fak only in response to LPA. These results indicate agonist-specific differences in the regulation of pathways mediating the tyrosine phosphorylation of pp125fak and other target proteins.
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PMID:Regulation of endothelin-1- and lysophosphatidic acid-stimulated tyrosine phosphorylation of focal adhesion kinase (pp125fak) in Rat-1 fibroblasts. 751 10

Thrombin stimulates G protein-coupled signaling pathways in target cells by proteolytic cleavage of its seven transmembrane domain receptor. Protein tyrosine phosphorylation is also stimulated by the protease via poorly defined mechanisms. In human platelets, thrombin has been shown to activate the nonreceptor tyrosine kinase Src. To elucidate the signal transduction pathways involved in transmission of thrombin's cellular effects, we have examined the ability of thrombin to activate Src family tyrosine kinases in a growth-responsive line of lung fibroblasts (CCL39 cells). We report here that thrombin induces a rapid (< or = 30 s) and transient increase in the kinase activity of Src and Fyn as determined by autophosphorylation in immune complex kinase assays. Activation is mediated by the G protein-coupled thrombin receptor since a synthetic peptide agonist of the receptor mimics thrombin action. The involvement of one or more G proteins in this response was confirmed by the observation that thrombin's effect is partially sensitive to pertussis toxin. Furthermore, both alpha 2-adrenergic and muscarinic m1 receptors are able to increase Src kinase activity via pertussis toxin-sensitive and -insensitive G proteins, respectively. These findings suggest that nonreceptor tyrosine kinases of the Src family may represent a novel effector system linking G protein-coupled receptors to downstream activation of Ras and the mitogen-activated protein kinase cascade.
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PMID:Activation of Src family kinase activity by the G protein-coupled thrombin receptor in growth-responsive fibroblasts. 752 55


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