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 effects of prostaglandin F2 alpha (PGF2 alpha) on intracellular Ca2+ concentration ([Ca2+]i) and inositol phosphate (IP) generation in human myometrial cells were evaluated and compared to the effects of oxytocin. Basal [Ca2+]i levels were 146 and 153 nM in the absence and presence of 1 mM extracellular Ca, respectively. In Ca-containing medium, both PGF2 alpha and oxytocin significantly (P less than 0.01) increased [Ca2+]i over control values, eliciting half-maximal stimulation (ED50) at 4 and 1 nM, respectively. In Ca-free medium the potency of PGF2 alpha to raise [Ca2+]i was drastically reduced (ED50, 2 microM), whereas that of oxytocin remained the same, although maximal responses were markedly decreased. PGF2 alpha had no effect on total IP production in the concentration range that significantly raised [Ca2+]i. However, at a 100 times higher concentration (10 microM), PGF2 alpha produced a maximum 48% increase in total IP, with a rapid (15-30 s) rise in IP3 and IP2, followed by IP1. A similar increase in IP production was obtained when [Ca2+]i levels were raised by A23187 to the same level as that obtained with 10-50 microM PGF2 alpha. The effect of PGF2 alpha was dependent on extracellular Ca and could be suppressed by verapamil, but not by pertussis toxin, or phorbol ester. In contrast, the potencies of oxytocin to raise IP and [Ca2+]i were similar and independent of extracellular Ca2+, and could be suppressed by pertussis toxin and phorbol ester, but not by verapamil. These data provide evidence that in isolated human myometrial cells, PGF2 alpha and oxytocin trigger an increase in [Ca2+]i by different mechanisms. The action of PGF2 alpha depends on extracellular Ca2+, whereas oxytocin activates the G-protein-dependent phospholipase-C-IP3-Ca2+ signal-transducing pathway, complemented by the influx of extracellular Ca2+.
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PMID:Regulation of intracellular free calcium in human myometrial cells by prostaglandin F2 alpha: comparison with oxytocin. 222 83

Dopamine-1 (DA-1) receptors have been found in renal tubular membranes which stimulate both adenylate cyclase and phospholipase-C activity. In renal cortical plasma membrane preparations the DA-1 agonist SKF 82526, forskolin and NaF stimulated adenylate cyclase activity. 2',5'-dideoxyadenosine inhibited basal and DA-1 agonist stimulated adenylate cyclase activity. Forskolin, NaF, dibutyryl-cyclic AMP and 2',5'-dideoxyadenosine had no effect on basal or DA-1 agonist stimulated phospholipase-C activity in these membranes. These studies indicate that DA-1 agonist stimulates adenylate cyclase and phospholipase-C activities independently. Phospholipase-C activity was also increased by the nonhydrolyzable GTP analog, guanosine-5'-O-(3-thiophosphate). When DA-1 agonist and guanosine-5'-O-(3-thiophosphate) were added together there was a slight but significant increase in phospholipase-C activity. This increase was inhibited in the presence of guanosine-5'-O-(2-thiodiphosphate). DA-1 stimulated phospholipase-C activity was found to be insensitive to both cholera and pertussis toxins. The present studies indicate a cyclic AMP independent transduction pathway for DA-1 receptor mediated through a guanine nucleotide regulatory protein associated phospholipase-C.
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PMID:The dopamine-1 agonist, SKF 82526, stimulates phospholipase-C activity independent of adenylate cyclase. 256 86

Cross-linking of membrane immunoglobulin, the B cell receptor for antigen, activates the phosphoinositide signal transduction pathway. The initial event in this pathway is the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP2) by phospholipase C. This reaction yields two intracellular second messengers, diacylglycerol, which activates protein kinase C, and inositol trisphosphate, which causes an increase in cytoplasmic Ca2+. The experiments reported here demonstrate that activation of phospholipase C by membrane IgM (mIgM) involves a guanine nucleotide-dependent step. Saponin was used to permeabilize WEHI-231 B lymphoma cells and permit direct manipulation of nucleotide and Ca2+ concentrations. Very high levels of Ca2+ (greater than 100 microM) activated the phospholipase maximally without a requirement for cross-linking of mIgM. However, at much lower, physiologically relevant Ca2+ concentrations (100 to 500 nM), receptor-stimulated PtdInsP2 hydrolysis could be demonstrated. The ability of anti-IgM antibodies to activate phospholipase C in permeabilized WEHI-231 cells was greatly increased by nonhydrolyzable guanosine 5'-triphosphate (GTP) analogues (guanosine-5'-O-(3-thiotriphosphate) or 5'-guanylylimidodiphosphate), but not by guanosine diphosphate or guanosine diphosphate analogues or by a nonhydrolyzable analogue of adenosine triphosphate. This specificity for GTP analogues is consistent with the hypothesis that a GTP-binding regulatory protein analogous to those that couple receptors to adenylate cyclase is involved in the activation of phospholipase C by mIgM in WEHI-231 B lymphoma cells. In order to characterize this putative GTP-binding component, we examined the ability of pertussis toxin and cholera toxin to affect anti-IgM-stimulated inositol phosphate production. These bacterial toxins covalently modify and modulate the activity of various GTP-binding regulatory proteins and in some cell types can block receptor-stimulated PtdInsP2 breakdown. In WEHI-231 B lymphoma cells, neither toxin blocked signaling by mIgM. Thus mIgM appears to be coupled to the phosphoinositide signaling pathway by a GTP-dependent component that is insensitive to both pertussis toxin and cholera toxin.
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PMID:Involvement of a guanine-nucleotide-binding component in membrane IgM-stimulated phosphoinositide breakdown. 282 10

Exposure of FRTL-5 thyroid cells to ATP (1 microM to 1 mM) resulted in the stimulation of I- efflux in association with the induction of inositol trisphosphate production and intracellular Ca2+ mobilization. Nonhydrolyzable ATP derivatives, ADP and GTP, were also as effective in magnitude as ATP, whereas neither AMP nor adenosine exerted significant effect on I- efflux, suggesting a P2-purinergic receptor-mediated activation of I- efflux. Treatment of the cells with the islet-activating protein (IAP) pertussis toxin, which ADP-ribosylated a 41,000 mol wt membrane protein, effectively suppressed the phosphoinositide response to ATP in addition to ATP-dependent I- efflux at agonist concentrations below 10 microM. In contrast, the I- efflux stimulated by TSH, A23187, or phorbol myristate acetate was insusceptible to IAP. The IAP substrate, probably GTP-binding protein, is hence proposed to mediate the activation of P2-purinergic receptor-linked phospholipase-C in FRTL-5 cells. However, the responses to ATP, its nonhydrolyzable derivatives, or ADP at the higher agonist concentrations, especially above 100 microM, were only partially inhibited by IAP, even though the IAP substrate was totally ADP ribosylated by the toxin. The responses to GTP in the whole concentration range tested were not influenced by IAP treatment. Thus, signals arising from the P2-receptor might be transduced to phospholipase-C by two different pathways, i.e. IAP-sensitive and insensitive ones, and result in the stimulation of I- efflux.
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PMID:Inhibition by islet-activating protein, pertussis toxin, of P2-purinergic receptor-mediated iodide efflux and phosphoinositide turnover in FRTL-5 cells. 284 Feb 60

The role of guanine nucleotide-binding proteins (G proteins) in the cAMP-dependent action of serotonin (5-HT) and the antagonistic action of the neuropeptide Phe-Met-Arg-Phe-NH2 (FMRF-amide), mediated by the lipoxygenase metabolites of arachidonic acid, was investigated in Aplysia sensory neurons. Intracellular injection of guanosine 5'-[gamma-thio]triphosphate (GTP[gamma-S]) mimics the hyperpolarizing action of FMRF-amide due to activation of the S K+ current and alters the transient response to FMRF-amide into an irreversible (or only partially reversible) response. At higher concentrations, GTP[gamma-S] occludes the response to FMRF-amide. Injection of activated pertussis toxin inhibits the response to FMRF-amide but not to 5-HT. Injection of guanosine 5'-[beta-thio]diphosphate inhibits the response to FMRF-amide by approximately equal to 50% and completely blocks the response to 5-HT. Three lines of evidence suggest that the FMRF-amide-activated G protein is involved at an early stage of the arachidonic acid cascade, prior to the release of arachidonate. (i) Pertussis toxin injection blocks the hyperpolarizing response to FMRF-amide but not to exogenously applied arachidonic acid. (ii) Two blockers of the arachidonic acid cascade inhibit the hyperpolarizing responses to both FMRF-amide and GTP[gamma-S] (and unmask a 5-HT-like depolarizing response to the nucleotide). (iii) Concentrations of GTP[gamma-S] that alter the kinetics of the FMRF-amide response have no effect on the hyperpolarizing response to arachidonic acid. We conclude that a pertussis toxin-sensitive G protein most likely acts to couple the FMRF-amide receptor to phospholipase activation and arachidonic acid release, whereas a pertussis toxin-insensitive G protein couples the 5-HT receptor to adenylate cyclase.
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PMID:Role of two different guanine nucleotide-binding proteins in the antagonistic modulation of the S-type K+ channel by cAMP and arachidonic acid metabolites in Aplysia sensory neurons. 284 23

We have presented evidence indicating that P2-purinergic receptors may activate the polyphosphoinositide-phospholipase C in HL60 cells via the mediation of a pertussis-toxin-sensitive GTP-binding protein, which also mediates the actions of chemotactic peptide receptors in these and other phagocytic white blood cells. However, our data also suggest that these same receptors can be coupled to the phospholipase via an additional pertussis-toxin-insensitive mechanism. This latter finding raises the possibility that undifferentiated HL60 cells express two distinct GTP-binding proteins coupled to phospholipase C; one of these is very likely to be the GHL/GC protein recently isolated from this cell line. Significantly, the data of Oinuma et al. and Falloon et al. indicate that expression of the 40-kDa alpha-subunit/toxin substrate increases upon differentiation of HL60 cells along the granulocyte pathway. It would be interesting to determine whether expression of the putative pertussis-toxin-insensitive G-protein decreases with differentiation of these and other myelomonocytic progenitor cells. Such studies, which are now in progress, should be facilitated by the fact that the P2-purinergic receptors appear to be expressed in myelopoietic cells from the promyelocytic/promonocytic stages through the terminally differentiated stages represented by circulating neutrophils and monocytes.
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PMID:Activation of the inositol phospholipid signaling system by receptors for extracellular ATP in human neutrophils, monocytes, and neutrophil/monocyte progenitor cells. 285 20

Leukocyte activation by chemoattractants provides an important model to study the biochemical mechanisms of stimulus-response coupling in these cells. Well-defined chemotactic factors induce readily quantifiable responses in phagocytic leukocytes. These include directed migration and the production and release of toxic substances including oxygen radicals and lysosomal enzymes. The development of radiolabeled synthetic oligopeptides with potent chemotactic activity allowed the demonstration of chemoattractant receptors on polymorphonuclear leukocytes (PMNs) as well as macrophages. In membrane preparations from these cells, these receptors exist in high- and low-affinity states which are regulated by guanosine di- and triphosphates. This suggested that chemoattractant receptors interact with guanine nucleotide regulatory proteins (N or G proteins). Although chemoattractants elicit a rapid but transient increase in intracellular cAMP levels, they neither stimulate nor inhibit membrane-bound adenylate cyclase, suggesting a novel role for N proteins in certain receptor-transduction mechanisms. Stimulation of phagocytes by chemoattractants is also associated with a rapid increase in cytosolic Ca2+ concentrations ([ Ca2+]i) which appears to result from the production of inositol 1,4,5-triphosphate (IP3) as a consequence of the diesteric cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2). Treatment of phagocytes with pertussis toxin (PT), which ADP-ribosylates and thereby inactivates certain N proteins, abolishes the cells' responsiveness to chemoattractants. More direct evidence for a role of a PT-sensitive N protein in leukocyte activation was provided by the demonstration that chemoattractants stimulate the hydrolysis of PIP2 in PMN membranes only in the presence of GTP. This receptor-mediated hydrolysis of PIP2 is not observed in plasma membranes prepared from PT-treated PMNs. Therefore, these studies suggest that occupancy of chemoattractant receptors activates a PT-sensitive N protein. The activated N protein shifts the Ca2+ requirement for phospholipase C activity from supraphysiological levels to ambient cytosolic Ca2+ concentrations. Cleavage of PIP2 results in the formation of the second messenger molecules, IP3 and 1,2-diacylglycerol, which can initiate cellular activation. These messengers also seem to activate responses which feed back to attenuate receptor stimulation of phospholipase.
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PMID:Role of guanine nucleotide regulatory protein in polyphosphoinositide degradation and activation of phagocytic leukocytes by chemoattractants. 302 89

Many hormones elicit effects on target cells by stimulating the enzyme phospholipase-C, which catalyzes the hydrolysis of phosphoinositides to the intracellular second messengers diacylglycerol and inositol phosphates. The present study examined the roles of FSH and guanine nucleotide-binding proteins (G-proteins) in regulating the hydrolysis of phosphoinositides in Sertoli cells. Sertoli cell cultures prepared from 16- to 18-day-old rats were incubated for 24 h with myo-[2-3H] inositol to label endogenous phospholipids. Treatment of cells from 0.5-20 min with preparations of ovine FSH ranging in potency from 1-60 times that of NIH FSH S1 did not affect accumulation of inositol phosphates. Levels of total [3H]inositol phosphates [[3H]inositol mono-, di-, and triphosphates (IP, IP2, and IP3)] in FSH-treated cultures was 75-120% the levels in control cultures over the various time intervals studied. Addition of testosterone and the combination of testosterone plus retinoic acid, agents that have been shown to potentiate effects of FSH in other systems, did not affect accumulation of inositol phosphates in response to FSH. In contrast to the lack of effect on accumulation of inositol phosphates, FSH stimulated 4- to 11-fold increases in estradiol secretion over 24 h of culture, indicating that Sertoli cells were viable and responsive to FSH. AIF4- has been shown to activate G-proteins involved in regulation of adenylate cyclase activity. In the present study, AIF4- induced 4- to 5-fold increases in IP, IP2, and IP3 in experiments wherein FSH had no effect. Pretreatment of Sertoli cells with pertussis toxin (100 and 1000 ng/ml) for 24 h inhibited fluoride-induced generation of IP, IP2, and IP3 by 24-51%. Similar treatment with cholera toxin had no effect on basal or fluoride-induced generation of IP2 or IP3, but increased fluoride-induced generation of IP by 20-34%. These results suggest that phospholipase-C activity in Sertoli cells is modulated by a pertussis toxin-sensitive G-protein(s), but does not appear to be affected by FSH.
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PMID:Regulation of the phosphoinositide pathway in cultured Sertoli cells from immature rats: effects of follicle-stimulating hormone and fluoride. 313 93

The mechanisms of activation of cytoplasmic phospholipase A2 (cPLA2) are complex and incompletely defined. In Chinese hamster ovary (CHO) cells, receptor stimulation of cPLA2 is due to the interaction of pathways involving the alpha subunits of at least two guanine-nucleotide-binding (G) proteins, G alpha i2 and G alpha q. Activation of cPLA2 is inhibited by pertussis toxin and G alpha i2 mutants. In addition, activation of phospholipase C via G alpha q results in increased intracellular calcium ([Ca2+]i) and activation of protein kinase C, both of which interact with and activate cPLA2. The present study was undertaken to analyze the mechanism of interaction of G alpha i2 with the phospholipase-C-stimulated pathway in the activation of cPLA2. We addressed this question using a dominant negative G alpha i2 mutant, [G203T]G alpha i2, in which Gly203 is mutated to Thr. [G203T]G alpha i2 inhibits ATP receptor activation of cPLA2. The effect of [G203T]G alpha i2 was specific to G alpha i2-activated pathways, as shown by its lack of effect on other purinergic receptor stimulated pathways: ATP stimulation of [Ca2+]i or mitogen-activated protein kinase phosphorylation is unaltered by [G203T]G alpha i2. We addressed the possibility that the activation of cPLA2 by Ca2+ and/or protein kinase C is dependent on G alpha i2. Activation of cPLA2 by the Ca2+ ionophore, ionomycin, was inhibited by 61 +/- 9% (n = 5) in [G203T]G alpha i2-expressing cells; however the ionomycin-induced [Ca2+]i rise was unaffected by [G203T]G alpha i2. Thus, [G203T]G alpha i2. specifically inhibits Ca2+ activation of cPLA2. In contrast, activation of cPLA2 via protein kinase C by phorbol 12-myristate 13-acetate was unaffected by [G203T]G alpha i2. Our results demonstrate that Ca2+ but not phorbol ester activation of cPLA2 in CHO cells is G alpha i2-dependent. The possibility is discussed that G alpha i2 is downstream of Ca2+ but upstream of protein kinase C activation of cPLA2.
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PMID:The guanine-nucleotide-binding protein subunit G alpha i2 is involved in calcium activation of phospholipase A2. Effects of the dominant negative G alpha i2 mutant, [G203T]G alpha i2, on activation of phospholipase A2 in Chinese hamster ovary cells. 760 Oct 96

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


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