UMLS:C0043167 - FACTA Search

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

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

The regulation of phospholipase A2 by G protein-coupled receptors is examined in CHO cells which normally express the purinergic receptor and have been transfected with bovine rhodopsin. The purinergic receptor has been reported to activate both phospholipase C and phospholipase A2 in this cell line. In contrast, bovine rhodopsin by itself is not able to activate phospholipase A2. However, the photoreceptor does potentiate purinergic receptor-mediated phospholipase A2 activation in a light-dependent manner. Both the purinergic receptor stimulation of phospholipase A2 and the enhanced activity mediated by rhodopsin are completely pertussis toxin-sensitive, suggesting the regulation of phospholipase A2 by a member of the Gi family of G proteins. Both of these receptors also inhibit adenylyl cyclase activity. Rhodopsin-mediated inhibition of adenylyl cyclase is pertussis toxin-sensitive, whereas inhibition by the purinergic receptor is calcium-sensitive but not pertussis toxin-sensitive. These results suggest (1) that rhodopsin is similar to other receptors that normally couple to Gi when expressed in cultured cells and (2) that regulation of adenylyl cyclase and PLA2 in CHO cells by rhodopsin and the purinergic receptor occur via distinct pathways.
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PMID:The coupling of pertussis toxin-sensitive G proteins to phospholipase A2 and adenylyl cyclase in CHO cells expressing bovine rhodopsin. 781 32

P2Y purinergic receptors previously have been shown to couple either to activation of phospholipase C through a pertussis toxin-insensitive mechanism or to inhibition of adenylyl cyclase through pertussis toxin-sensitive members of the G1 family of G proteins. These and other pharmacological data strongly suggest that multiple P2Y purinergic receptors exist. Webb et al. [FEBS Lett. 324:219-225 (1993)] cloned a cDNA that, when expressed in frog oocytes, displayed the general pharmacological characteristics of a P2Y purinergic receptor but whose second messenger linkage was not resolved. We have now cloned the meleagrid (turkey) homologue of the previously cloned chick P2Y purinergic receptor and have stably expressed it in a heterologous human cell line (1321N1 astrocytoma cells) to establish its signaling properties. The purinergic receptor agonist 2-methylthio-ATP (2MeSATP) stimulated a marked activation of phospholipase C in 1321N1 cells stably expressing the meleagrid receptor. The order of potency of a series of analogues of ATP and ADP for stimulation of phospholipase C by the receptor expressed in 1321N1 cells [2MeSATP = 2-methylthio-ADP > adenosine 5'-O-(2-thio)diphosphate > ADP > 2-chloro-ATP = adenosine 5'-O-(3-thio)triphosphate > or = ATP > adenylyl-imidodiphosphate > UTP] was similar to that observed for P2Y purinergic receptors in turkey erythrocytes and many other tissues and was markedly different from those of the P2U and P2X purinergic receptor subtypes. Stimulation of inositol lipid hydrolysis by P2Y purinergic agonists was not affected by preincubation of cells with pertussis toxin. In contrast to its marked effects on phospholipase C activity, 2MeSATP caused only a small and variable inhibition of cAMP accumulation. Ribonuclease protection analysis of turkey tissues showed that this P2Y purinergic receptor is most highly expressed in blood and brain. Taken together, these results indicate that a phospholipase-C-activating P2Y purinergic receptor has been cloned and stably expressed in 1321N1 astrocytoma cells.
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PMID:Expression of a cloned P2Y purinergic receptor that couples to phospholipase C. 805 61

In rabbit renal cortical collecting tubule (CCT), perfused in vitro at 38 degrees C, ATP in concentrations of 10(-7) M and greater inhibits arginine vasopressin (AVP)-stimulated osmotic water permeability (Pf). The P1-purinergic receptor antagonist 8-phenyltheophylline did not attenuate the inhibitory action of ATP, and the poorly hydrolyzable ATP analogue, 5'-adenylylimidodiphosphate (AMP-PNP), mimicked the effect of ATP, arguing against an effect of ATP on a P1 receptor or the "P site." Purinergic receptor agonists inhibited AVP-stimulated Pf with the following rank order efficacy: ATP = ADP = UTP = AMP-PNP = alpha, beta-methylene-ATP > 2-methylthio-ATP >> AMP > adenosine, consistent with the pharmacology of a "nucleotide" receptor subtype. Pertussis toxin pretreatment attenuated the action of 10(-5) and 10(-6) MATP; however, 10(-4) MATP failed to inhibit the hydrosmotic action of forskolin or 8-bromoadenosine 3',5'-cyclic monophosphate. Pretreatment with the phosphodiesterase inhibitor RO20-1724 or indomethacin did not inhibit the action of ATP. Staurosporin and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester significantly attenuated the inhibition of Pf by lower concentrations of ATP. These data suggest that ATP activates nucleotide receptors on the CCT, mobilizing intracellular Ca2+, which inhibits the hydrosmotic action of AVP.
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PMID:ATP inhibits the hydrosmotic effect of AVP in rabbit CCT: evidence for a nucleotide P2u receptor. 806 90

The effect of purinergic receptor agonists on arachidonic acid release was investigated in [3H]arachidonic acid-prelabeled human airway epithelial cells. Exposure of bronchial epithelial BEAS39 cells to extracellular ATP resulted in a marked release of unesterified [3H]arachidonic acid with maximal effect observed within 60-90 s. [3H]diacylglycerol and [3H]phosphatidic acid accumulated in parallel with [3H]arachidonic acid. ATP-stimulated [3H]arachidonic acid release with a K0.5 of 9 +/- 2 microM and UTP was equipotent; no effect was observed with P2Y- or P2X-purinergic receptor agonists or with adenosine. Similar results were obtained with primary cultures of normal human nasal epithelium, CF/T43 and HBE1 airway epithelial cell lines derived from a cystic fibrosis patient and from a normal donor, respectively, and HT-29 human colon carcinoma cells. ATP stimulated inositol phosphate formation in BEAS39 cells with a concentration dependence identical to that for [3H]arachidonic acid release. The effect of ATP on both [3H]arachidonic acid release and inositol phosphate formation was equally inhibited by pertussis toxin. The Ca2+ ionophore A-23187 mimicked the effects of ATP or UTP on arachidonic acid release, and a marked inhibitory effect was observed with thapsigargin. The protein kinase C inhibitor staurosporine partially inhibited ATP-stimulated [3H]arachidonic acid release. These data are consistent with the hypothesis that phospholipase A2 activation is secondary to P2U-purinergic receptor stimulation of D-myoinositol 1,4,5-trisphosphate production and calcium mobilization from intracellular stores.
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PMID:Calcium-dependent release of arachidonic acid in response to purinergic receptor activation in airway epithelium. 814 Dec 54

We studied the effect of adenosine on prolactin secretion by the anterior pituitary, and the transduction mechanisms whereby the purine exerts its action. Adenosine inhibited prolactin release in basal and in vasoactive intestinal peptide (VIP)- or TRH-stimulated conditions. Pertussis toxin pretreatment reduced the inhibition of VIP-stimulated prolactin secretion which was induced by adenosine, while it completely abolished the effect of the purine on TRH-evoked prolactin release. In membrane preparations of anterior pituitary cells, adenosine reduced the adenylate cyclase activity stimulated by VIP. Such an inhibition was not blocked by pertussis toxin pretreatment. Furthermore, the purine reduced TRH-stimulated inositol phosphate production in cultured anterior pituitary cells, an effect that was reversed by pretreatment with pertussis toxin. In addition, the nucleoside did not significantly affect the TRH-induced rise in intracellular calcium. In conclusion, our data show that adenosine inhibits prolactin secretion, acting on purinergic receptors coupled to the adenylate cyclase enzyme and phospholipase C. The effect of the nucleoside on adenylate cyclase seems to be achieved either by the involvement of an adenosine receptor coupled to the catalytic subunit of the enzyme via a pertussis toxin-sensitive G protein, or by the activation of a site directly coupled to the catalytic subunit of the adenylate cyclase (the P site). Its effect on phospholipase C seems to be mediated by a purinergic receptor coupled to the intracellular effector via a pertussis toxin-sensitive G protein.
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PMID:Direct effect of adenosine on prolactin secretion at the level of the single rat lactotroph: involvement of pertussis toxin-sensitive and -insensitive transducing mechanisms. 814 40

Outer hair cells (OHC) of the mammalian cochlea are thought to preprocess the sound signal by active movements, which can be induced by electrical or chemical stimulation, e.g. depolarization evoked by high [K+] or increased cytoplasmic [Ca2+]. Extracellular ATP has been found to induce cytoplasmic [Ca2+] increases in OHC but involved mechanisms have not been elucidated. Cytoplasmic [Ca2+] was measured in non-enzymatically isolated single OHC using Fura-2 microspectrometry. Results, using ATP/derivatives and other P2-purinergic receptor (P2R) ligands, as well as Ca(2+)-channel blockers and pertussis toxin, revealed several signal transduction pathways that increase cytoplasmic [Ca2+] in OHC: a P2-purinergic receptor (P2R)--G-protein--effector (phospholipase C or an ion channel) system and a voltage-dependent Ca2+ channel. Agonist potency studies denote a pattern analogous to that found in skeletal muscle, i.e. ATP-alpha-S > ATP = 2-methyl-S-ATP >> ADP > alpha,beta-methylene-ATP, but no activation by ADP beta F or UTP, leaving a choice of P2y or P2zR subtypes. The latter possibility gained strength from calculations showing that up to 8% of ATP may have formed the P2zR agonist ATP4- in the experimental medium. Experiments in Ca(2+)-free medium and with pertussis toxin revealed that the main Ca2+ source was intracellular. Pertussis toxin did not affect [Ca2+] increase induced by carbachol. Acetylcholine, administered a few seconds before ATP, did not affect total cytoplasmic [Ca2+] increases. Induced cytoplasmic [Ca2+] increases were high enough (> 500 nM at 50 microM ATP/derivatives) to hyperpolarize the OHC membrane by opening K(+)-channels and decreased little with time.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:ATP-induced cytoplasmic [Ca2+] increases in isolated cochlear outer hair cells. Involved receptor and channel mechanisms. 815 3

Secretion of catecholamines by rat PC12 cells is strongly stimulated by extracellular ATP via a P2-type purinergic receptor. ATP-induced norepinephrine release was inhibited 80% when extracellular Ca2+ was absent. Only four nucleotides, ATP, ATP gamma S, benzoylbenzoyl ATP (BzATP), and 2-methylthio-ATP, gave substantial stimulation of norepinephrine release from PC12 cells. ATP-induced secretion was inhibited by Mg2+, and this inhibition was overcome by the addition of excess ATP suggesting that ATP4- was the active ligand. ATP-induced secretion of catecholamine release was enhanced by treatment of cells with pertussis toxin or 12-O-tetradecanoylphorbol 13-acetate. The stimulatory effects of 12-O-tetradecanoylphorbol 13-acetate and pertussis toxin on norepinephrine release were additive. After brief exposure of intact cells to the photoaffinity analog, [alpha-32P]BzATP, two major proteins of 44 and 50 kDa and a minor protein of 97 kDa were labeled. An excess of ATP gamma S and BzATP but not GTP blocked labeling of the proteins by [32P]BzATP. Labeling of the 50-kDa protein was more sensitive to competition by 2-methylthio-ATP than the other labeled proteins, suggesting that the 50-kDa protein represents the P2 receptor responsible for ATP-stimulated secretion in these cells.
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PMID:ATP-induced secretion in PC12 cells and photoaffinity labeling of receptors. 822 85

Adenine nucleotides inhibited isoproterenol- and forskolin-stimulated cyclic AMP accumulation in C6-2B rat glioma cells. Inhibition occurred in the presence of a phosphodiesterase inhibitor, and no effect of adenine nucleotides was observed in direct measurements of phosphodiesterase activity in intact cells. Pretreatment of C6-2B glioma cells with pertussis toxin blocked the inhibitory effects of P2Y-purinergic receptor agonists. The pharmacological specificity for a series of ATP and ADP analogs (2-methylthioadenosine 5'-triphosphate > or = 2-methylthioadenosine 5'-diphosphate > adenosine 5'-O-(2-thiodiphosphate) > 2-chloro-adenosine 5'-triphosphate = ADP = adenosine 5'-O-(3-thiotriphosphate) > ATP > UTP) was similar to that expected of a P2Y-purinergic receptor; the P2X-purinergic receptor agonists, alpha,beta-methyleneadenosine 5'-triphosphate and beta,gamma-methylene-adenosine 5'-triphosphate, had no effect. Because activation of phospholipase C occurs in response to P2-purinergic receptor activation in many target tissues, the effects of P2Y-receptor agonists on inositol phosphate accumulation were measured in C6-2B cells. No evidence for P2Y-purinergic receptor-mediated regulation of inositol lipid metabolism was observed under conditions where muscarinic cholinergic receptor activation or AIF4-markedly increased inositol phosphate accumulation. These results suggest that a P2-purinergic receptor subtype with distinct signaling properties exists on C6-2B rat glioma cells. Although this receptor expresses the general pharmacological specificity of a phospholipase C-coupled P2Y-purinergic receptor, it may represent a unique receptor subtype since it inhibits adenylyl cyclase.
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PMID:Identification of a P2Y-purinergic receptor that inhibits adenylyl cyclase. 826 74

1. The effects of externally applied micromolar concentrations of adenosine 5'-triphosphate (ATP) on Ca2+ currents (ICa) were studied in whole-cell clamped adrenaline-secreting chromaffin cells. 2. Ca2+ currents in chromaffin cells activated at about -40 mV, reached a maximum at 0 mV and had an apparent reversal potential at +50 to +60 mV, indicating the existence of only high voltage-activated Ca2+ channels. 3. ATP blocked Ca2+ current rapidly, reversibly and in a concentration-dependent manner (10(-9)-10(-4) M). 4. ATP did not completely block Ca2+ current even at the highest concentrations used (100 microM). The remaining component of Ca2+ current was characterized by slower activation and inactivation kinetics. 5. ATP blocked ICa even in the presence of nisoldipine and/or omega-conotoxin GVIA, suggesting that its modulatory role is not specific for L- and/or N-type Ca2+ channels. 6. Other adenine nucleotides also blocked the Ca2+ current partially. The order of potencies was ATP > or = ADP > AMP >> adenosine, indicating that the ATP effects are most probably mediated by a P2-type purinergic receptor. 7. Dialysis of the cells with an intracellular solution containing 1 mM guanosine 5'-O-thiodiphosphate (GDP-beta-S) or pre-incubation of the cells with pertussis toxin (PTX) blocked the inhibitory effects of ATP. 8. Intracellular application of the non-hydrolysable GTP analogue guanosine 5'-O-(3'-thiotriphosphate) (GTP-gamma-S; 50 microM) also decreased ICa in a manner similar to that seen for ATP and significantly reduced the ATP inhibitory effect. 9. Conditioning pulses to potentials positive to +80 mV partly reversed the inhibitory effects of ATP on the Ca2+ current. The prepulse-induced enhancement of ICa depended on [GTP]i-related G protein activity such that concentrations larger than 200 microM GTP, or GTP-gamma-S (50 microM) were required for significant prepulse potentiation of the Ca2+ current, while dialysis with GDP-beta-S prevented it. 10. We conclude that the ATP, co-released with catecholamines in the intact adrenal gland, may inhibit the secretory process by down-regulating the Ca2+ channel via a P2-type purinergic receptor coupled to a PTX-sensitive G protein.
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PMID:ATP modulation of calcium channels in chromaffin cells. 830 43

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