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

Phospholipase D (PLD) can be activated by a variety of receptor agonists in different cell types. However, an effect of prostaglandins (PGs) on the activity of this enzyme has not been demonstrated previously. In this study, we found that PGE1 could stimulate PLD in human erythroleukemia cells, as measured by phosphatidylethanol formation, with an ED50 of 3.5 x 10(-7) M. PGE2 was also active, but other PGs including prostacyclin, PGD2 and PGF2, had no effect. PGE1 also elicited cyclic AMP production over the same concentration range that activated PLD. However, it is unlikely that cyclic AMP per se is responsible for PGE-induced PLD activation, because PLD could be substantially activated by PGE2 at concentrations (0.1-1 microM) which did not stimulate cyclic AMP production. Furthermore, no increase of phosphatidylethanol formation could be observed when cells were treated with other adenylyl cyclase-activating agents such as prostacyclin, forskolin and vasoactive intestinal peptide. In Ca+(+)-free medium, PLD activation by PGE1 and PGE2 was greatly reduced, indicating that their effect was through a Ca+(+)-dependent pathway. Pretreatment of cells with pertussis toxin abolished PGE1- and PGE2-stimulated PLD activity, implying the involvement of a G protein in the PGE-mediated signal transduction pathway. Our results not only indicate that E-series PGs may initiate some of their cellular effects through a novel pathway, activation of PLD, but also suggest that PGE-stimulated PLD activity in human erythroleukemia cells is Ca+(+)-dependent and is regulated via a pertussis toxin-sensitive G protein.
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PMID:Activation of phospholipase D by E-series prostaglandins in human erythroleukemia cells. 165 Aug 37

1. The effects of increases in intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) on mitogen-induced generation of inositol phosphates and increases in intracellular Ca2+ concentration were investigated in human peripheral blood mononuclear leukocytes (MNL). 2. The mitogens concanavalin A (Con A), pokeweed mitogen (PWM) and phytohaemagglutinin (PHA) concentration-dependently stimulated generation of inositol phosphates. Catecholamines inhibited this process with an order of potency: isoprenaline greater than adrenaline greater than noradrenaline indicating involvement of beta 2-adrenoceptors. This order of potency was also consistent with the catecholamine potencies for stimulating the generation of cyclic AMP. 3. In addition to catecholamines, the cyclic AMP formation-stimulating agents prostaglandin E1 (PGE1) and forskolin concentration-dependently inhibited mitogen-induced inositol phosphate generation, too. Moreover, the inhibitory effect of isoprenaline was potentiated by co-incubation with the phosphodiesterase inhibitor isobutylmethylxanthine demonstrating that these inhibitory effects were mediated by cyclic AMP. 4. Con A and PHA concentration-dependently increased the intracellular Ca2+ concentration in human MNL (assessed by the fluorescent indicator dye Fura-2). This increase was almost completely blocked by chelation of extracellular Ca2+, demonstrating influx rather than mobilization from intracellular stores. 5. The elevation of intracellular Ca2+ was not blocked by pretreatment with pertussis toxin, 100 ng ml-1, for 16 h. 6. Isoprenaline, PGE1, and forskolin, however, inhibited the mitogen-stimulated elevation of intracellular Ca2+. This inhibition was enhanced by the phosphodiesterase inhibitors isobutylmethylxanthine and Ro 20-1724, demonstrating mediation by cyclic AMP. 7. We conclude that catecholamines and other cyclic AMP increasing agents can inhibit mitogen-stimulated generation of inositol phosphates and elevation of intracellular Ca2+ in resting human MNL.
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PMID:Cyclic AMP counteracts mitogen-induced inositol phosphate generation and increases in intracellular Ca2+ concentrations in human lymphocytes. 165 68

1. The effect of bacterial toxins on bradykinin-triggered release of arachidonic acid was studied in serum-deprived human foreskin (HSWP) fibroblasts prelabelled with [3H]-arachidonic acid. An 18-h exposure of HSWP cells to cholera toxin, pertussis toxin, or forskolin enhanced the bradykinin-stimulated release of arachidonic acid and metabolites. 2. Prolonged treatment of HSWP cells with these agents also caused a 3 to 4 fold rise in cell surface [3H]-bradykinin binding. The rise was inhibited by concurrent incubation with cycloheximide or actinomycin D. In addition, cholera toxin and foreskolin increased [3H]-bradykinin binding in wildtype PC12 cells, but not in mutant PC12 cells with reduced cyclic AMP-dependent protein kinase type II activity. 3. In conclusion, cholera toxin, pertussis toxin and forskolin enhanced arachidonic acid release in response to bradykinin, and increased the number of bradykinin receptors in HSWP fibroblasts. A cyclic AMP-dependent mechanism appears to mediate the actions of the toxins and forskolin.
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PMID:Regulation of bradykinin receptor level by cholera toxin, pertussis toxin and forskolin in cultured human fibroblasts. 165 71

1. After blocking K+ currents with 10 mM-tetraethylammonium (TEA) or TEA plus 250 microM-3,4-diaminopyridine (3,4-DAP). motor nerve terminal Ca2+ currents were recorded using focal extracellular electrodes. Two transmitters released from the terminal. ATP and acetylcholine (ACh), were then applied, and the effects on the nerve terminal Ca2+ current were measured. 2. ATP (50 microM) reduced the Ca2+ current by 34%, but this action is prevented when hydrolysis to adenosine is blocked by alpha,beta-methyladenosine 5'-diphosphate (200 microM). Thus, inhibition by ATP presumably occurs subsequent to ATP hydrolysis to adenosine. 3. Adenosine (50 microM) inhibited the terminal Ca2+ current by 29%. This was mimicked by the adenosine analogue L-phenylisopropyl adenosine (L-PIA) and blocked by theophylline (100 microM), which antagonizes adenosine receptors at micromolar concentrations. 4. ACh (100 microM) or the anticholinesterase methane sulphonyl fluoride (MSF; 1 mM) also depressed the terminal Ca2+ current. This response was mimicked by muscarine (100 microM) and antagonized by atropine (100 microM) or pirenzipine (4 microM), which is generally specific for M1 receptors. 5. Addition of Ba2+, which blocks adenosine-mediated K+ currents, had no effect on the inhibitory effects of either adenosine or ACh; similarly, neither adenosine nor ACh in the bath affected K+ current records obtained after blocking all inward currents with 10 mM-Co2+ and focal application of tetrodotoxin. 6. Incubation of the muscle for 4 h in pertussis toxin (10(-5) g ml-1) eliminated both adenosine- and ACh-induced inhibition of the terminal Ca2+ current. This result indicates the possible involvement of a G protein in the transduction of the feedback pathway. 7. Neither cyclic AMP analogues, the adenylate cyclase activator forskolin (10 microM), the phorbol ester phorbol 12-myristate 13-acetate (PMA; 3 microM) nor the diacylglycerol analogue 1,2-oleoylacetylglycerol (OAG; 3 microM) had any effect on adenosine- or ACh-induced depression of the terminal Ca2+ current. Therefore, pathways involving these particular second messengers are most probably not involved. 8. The effects of adenosine and ACh are non-additive. 9. These results indicate that ATP and ACh, which are released during exocytosis, may inhibit their own release through attenuation of the terminal Ca2+ current via autoreceptors coupled to a G protein.
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PMID:Autoreceptor-mediated purinergic and cholinergic inhibition of motor nerve terminal calcium currents in the rat. 165 22

The cellular basis for hormonal control of bone resorption is poorly understood. As the identifiable receptors for bone resorbing agents such as parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are located on osteoblasts rather than osteoclasts, the nature of cellular signaling is obscure. Here it is reported that exposure of fetal rat limb bones to pertussis toxin, a bacterial protein that inhibits certain GTP binding proteins (G-proteins) involved in signal transduction, markedly inhibits bone resorption elicited by PTH, 1,25(OH)2D3 and prostaglandin E2. Pertussis toxin does not block the inhibition of alkaline phosphatase activity by PTH or 1,25(OH)2D3, and it potentiates the cyclic AMP response to PTH. These data support the existence of a pertussis toxin-sensitive G-protein that participates in regulation of bone resorption. The putative G-protein is apparently not involved in the initial transduction of hormonal signals, but it may be part of a final common pathway through which the osteoclast is activated by agents with widely divergent initial actions.
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PMID:Pertussis toxin inhibits hormonal stimulation of bone resorption in fetal rat limb bones. 165 45

The muscarinic m1 and m2 receptors are functionally coupled to multiple effectors via distinct guanine nucleotide regulatory proteins (G-proteins) defined by their pertussis toxin (PTX) sensitivity. Both receptors are coupled to the hydrolysis of phosphoinositides (PI), whereas only the m2 receptors inhibit cAMP formation. This study examines how the selective interactions of these two receptors with G-proteins may govern their specific functional coupling to the two second messenger pathways. Murine fibroblasts (B82) transfected with the rat m1 or m2 receptor genes were used to test the PTX sensitivity of the m1 and m2 receptor-mediated pathways. It was found that the stimulation of PI hydrolysis and inhibition of cyclic AMP mediated by m2 receptors had similar PTX sensitivity (IC50 = 0.14 ng/ml and 0.26 ng/ml), whereas the m1-mediated PI hydrolysis was PTX insensitive. The EC50 value for carbachol in the m1 receptor-mediated PI hydrolysis was 9.5 microM, whereas those for the m2 receptor-mediated PI hydrolysis and inhibition of cyclic AMP formation were 0.3 microM and 1.2 microM, respectively. The potency of carbachol correlated well with its binding affinities for the two receptor subtypes. These results suggest that the m2 receptors are coupled to multiple pathways via PTX-sensitive G-proteins, which are distinct from those that interact with the m1 receptor. The formation of functional receptor-G-protein complexes may be selective and governed by the efficiencies in coupling between receptors and G-proteins.
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PMID:The m2 muscarinic acetylcholine receptors are coupled to multiple signaling pathways via pertussis toxin-sensitive guanine nucleotide regulatory proteins. 165 46

Human polymorphonuclear neutrophils (PMN) respond to ATP with an elevation in intracellular calcium and a marked enhancement of O2-production in response to stimulation by the chemotactic peptide N'-formyl-Met-Leu-Phe (FMLP). These pertussis toxin-sensitive pathways appear to be mediated by a nucleotide receptor(s) on the surface of human PMN. In the current study, we have examined the binding to intact human PMN of the ATP analog, adenosine 5'-O-(3-thio[35S] triphosphate) [( 35S]ATP gamma S). On the basis of Scatchard analysis, the binding of [35S]ATP gamma S involves at least two sites, one of high and one of low affinity. In the presence of sodium thiophosphate, a compound which did not affect intracellular increases in calcium induced by ATP or N'-formyl-Met-Leu-Phe, a significant fraction of the [35S]ATP gamma S binding was eliminated. This reduction involved both high and low affinity binding of [35S]ATP gamma S and was related to a reduction in numbers of binding sites. The Kd values for the high affinity binding site were unaffected by the presence of sodium thiophosphate, although the low affinity Kd values were numerically increased by 2-fold. In the presence of thiophosphate, [35S]ATP gamma S binding was specific, saturable, and reversible, and was related to a single class of high affinity (Kd = 36 +/- 19 nM) binding sites (184 +/- 144 sites/cell), together with a second class of low affinity (Kd = 1110 +/- 503 nM) binding sites (13,562 +/- 6,851 sites/cells). Competitive binding experiments, based on the ability of nucleotides and ATP analogs to block [35S]ATP gamma S binding to PMN, revealed a rank order of ATP gamma S greater than ATP greater than 2-MeS-ATP = 8-Bromo ATP greater than ADP = ITP greater than AMP-PCP = GTP much greater than CTP. A comparison between the ability of nucleotides to compete with [35S]ATP gamma S binding and their ability to induce a biologic response (elevation of intracellular calcium) revealed a close correlation (r2 = 0.83). These findings support the possibility of a common nucleotide PMN receptor functionally linked to a cellular response which involves increases in intracellular calcium.
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PMID:Adenosine-5'-O-(3-thiotriphosphate) binding to human neutrophils. Evidence for a common nucleotide receptor. 165 77

It has been proposed that the cytokine interleukin-1 beta (IL-1 beta), secreted by islet-infiltrating macrophages, may be involved in the pathogenesis of insulin-dependent diabetes mellitus by participation in beta-cell destruction. Addition of IL-1 beta to isolated pancreatic islets in vitro results in cytotoxic effects on beta-cell function, but there is little information on the intracellular events that convey the actions of the cytokine. In the present study, fetal rat pancreatic islets containing a high fraction of beta-cells were exposed in culture to IL-1 beta. It was found that IL-1 beta markedly decreased beta-cell DNA synthesis, insulin secretion and cyclic AMP content. In order to explore whether the decrease in cAMP resulted from IL-1 beta interaction with GTP-binding proteins coupled to adenylyl cyclase, islets were treated for 24 h with pertussis toxin prior to addition of cytokine. While this treatment restored the decrease in cAMP, the reduced DNA synthesis and insulin secretion persisted. Pertussis toxin treatment without the addition of IL-1 beta resulted in increases in cAMP, DNA synthesis and insulin secretion. Addition of the stimulatory cAMP analog Sp-cAMPS also increase DNA synthesis and insulin secretion, but failed to affect the decrease in these functions evoked by IL-1 beta. The protease inhibitor N alpha-p-tosyl-L-lysine chloromethyl ketone, recently shown to protect completely against IL-1 beta-induced suppression of insulin production and secretion, was found to markedly reduce DNA synthesis without affecting insulin secretion. When the protease inhibitor was combined with IL-1 beta, the suppressed secretion was counteracted while DNA synthesis inhibition was not. It is concluded that cAMP stimulates DNA synthesis and insulin secretion in beta-cells, but that the inhibitory effect of IL-1 beta on these functions cannot be ascribed to the decrease in cAMP evoked by the cytokine. However, the repressive effect of the cytokine on insulin secretion, but not DNA synthesis, may be prevented by protease inhibition.
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PMID:Inhibition of fetal rat pancreatic beta-cell replication by interleukin-1 beta in vitro is not mediated through pertussis toxin-sensitive G-proteins, a decrease in cyclic AMP, or protease activation. 165 27

Mouse neuroblastoma x rat glioma hybrid cells (N x G, 108CC15) were used to study the inhibitory effects of the synthetic opioid D-Ala2-D-Leu5-enkephalin (DADLE), somatostatin, adrenaline-alpha 2 and angiotensin II on voltage-dependent Ca(2+)-currents (ICa) using the patch-clamp technique in the whole-cell configuration mode. The inhibitory effects could be abolished by pretreatment of N x G cells with pertussis toxin or intracellular infusion of GDP beta S indicating an involvement of a pertussis toxin sensitive GTP-binding protein (G-protein), presumably Go. The effect of DADLE, the strongest inhibitor of ICa, was studied during dibutyryl cyclic AMP (dBcAMP) induced differentiation. Using omega-conotoxin GVIA (omega-CTX) and methoxyverapamil (D600) as specific Ca(2+)-channel blockers of the N- and L-type Ca(2+)-channels, it was found that in N x G cells DADLE predominantly induces inhibition of T- and N-type Ca(2+)-channels.
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PMID:Inhibitory modulation of fast and slow Ca(2+)-currents in neuroblastoma x glioma cells during differentiation. 165 35

Muscarinic receptor-linked Ca2+ mobilization and changes in cyclic AMP were studied in SH-SY5Y and IMR 32 human neuroblastoma cell lines. Muscarinic agonists acetylcholine, carbachol, methacholine and muscarine induced an increase in cytosolic free Ca2+ in a pertussis toxin (100 ng/ml)-insensitive manner in both cell lines. The ED50 values in IMR 32 cells (8-98 microM) were one order of magnitude higher than in SH-SY5Y cells (0.3-1.6 microM). Oxotremorine and pilocarpine failed to mobilize Ca2+ in IMR 32 cells. Pirenzepine antagonized carbachol-induced Ca2+ mobilization in SH-SY5Y cells with a Ki value in the range of 150-189 nM whereas the corresponding values in IMR 32 cells were 24-28 nM. Atropine inhibited a carbachol-stimulated increase in cytosolic Ca2+ with an equal potency in both cell lines (Ki 2-3 nM). Carbachol stimulated cyclic AMP (cAMP) accumulation in SH-SY5Y cells in a pertussis toxin-insensitive manner. In IMR 32 cells carbachol inhibited prostaglandin E1-stimulated cAMP accumulation. Treatment of IMR 32 cells with pertussis toxin abolished the inhibition of stimulated cAMP accumulation. These results suggest that in SH-SY5Y cells the M3 muscarinic receptor couples to both Ca2+ mobilization and stimulation of cAMP accumulation. In IMR 32 cells the M1 receptor seems to couple to Ca2+ mobilization whereas the inhibition of stimulated cAMP accumulation is coupled to a non-M1 subtype by an inhibitory G-protein.
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PMID:Differential coupling of muscarinic receptors to Ca2+ mobilization and cyclic AMP in SH-SY5Y and IMR 32 neuroblastoma cells. 165 23


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