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)

Angiotensin II (ANG II) was shown to modulate transport in the renal proximal tubule through both inhibition of adenylate cyclase and protein kinase C (PKC) activation. We evaluated the effects of ANG II on adenosine 3',5'-cyclic monophosphate (cAMP) content and Na-H exchange activity (amiloride-sensitive Na influx) in two strains of opossum kidney (OK) cells originating from different sources, OK-VD and OK-RR cells. In OK-VD cells, ANG II inhibited basal and parathyroid hormone (PTH)-induced cAMP generation in a pertussis toxin-sensitive manner and reversed PTH inhibition of Na-H exchange. These effects of ANG II were prevented by PD 123319, a selective nonpeptide antagonist of AT2 receptors. In contrast, DuP 753, which antagonizes selectively AT1 receptors, had no effect. In OK-RR cells, ANG II had no effect on cAMP content and decreased Na-H exchange activity. The effect of ANG II persisted in the presence of PTH but was abolished by PKC downregulation and by DuP 753, but not by PD 123319. In conclusion, two types of ANG II receptors, coupled to distinct signaling pathways, were expressed independently in OK cells originating from two different sources and mediated opposite effects of ANG II on Na-H exchange activity. Those models provide a powerful tool for studying the intracellular steps involved in the tubular effects of ANG II and to evaluate the effect of pharmacological inhibitors of ANG II binding to its receptors.
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PMID:Modulation of Na-H exchange activity by angiotensin II in opossum kidney cells. 133 86

In cultured cortical collecting duct (CCD) cells, exogenous prostaglandin E2 (PGE2) inhibited arginine vasopressin (AVP)-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production in a concentration-dependent manner. Although pertussis toxin (PT, 500 ng/ml) alone did not reverse the PGE2-dependent inhibition, PT and staurosporine, a protein kinase C inhibitor, together partially reversed the effect of exogenous PGE2. In contrast, PT completely reversed the inhibition of AVP-dependent cAMP production by sulprostone. These data suggest that exogenous PGE2 can inhibit AVP-stimulated cAMP production and that the inhibitory effects of PGE2 are mediated by staurosporine- and PT-sensitive component(s). Short-term (15-240 min) incubation with phorbol 12-myristate 13-acetate (PMA, 10(-7) M) inhibited PGE2-stimulated cAMP production. Long-term (20 h) incubation with PMA augmented PGE2-stimulated cAMP production. These data provide evidence for the maintenance of a PT-sensitive PGE2-dependent inhibitory pathway of cAMP production in cultured CCD cells. In addition, data are presented that support an inhibitory role for protein kinase C in the effects of PGE2 on the metabolism of cAMP in these cells.
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PMID:PGE2 regulates cAMP production in cultured rabbit CCD cells: evidence for dual inhibitory mechanisms. 133 88

Parafollicular (PF) cells of the thyroid gland are neural crest derivatives, which costore the neurotransmitter, 5-hydroxytryptamine (5-HT) with calcitonin. PF cells are located adjacent to follicular (F) cells within the basement membrane of thyroid follicles. It has been proposed that 5-HT serves an intercellular signalling function in the thyroid and that F cells are its target. This proposal was tested by using cell lines derived from PF (medullary thyroid carcinoma [MTC]) and F (FRTL-5) cells to study the mechanisms that mediate the secretion and action of 5-HT. Secretion of 5-HT by MTC cells was evoked by thyroid stimulating hormone, thyrotropin (TSH), elevated extracellular calcium (increases [Ca2+]e), or by agents that increase intracellular cAMP (increases [cAMP]i). When protein kinase C (PKC) was down-regulated by prolonged treatment of MTC cells with phorbol 12-myristate 13-acetate (PMA), or PKC was inhibited by staurosporin, the TSH- or PMA-evoked secretion of 5-HT was blocked; however, interference with PKC function did not affect 5-HT secretion evoked by increases [Ca2+]e or increases [cAMP]i. In the putative targets, FRTL-5 cells, 5-HT increased the turnover of phosphoinositides (PI), cytosolic calcium (increases [Ca2+]i), increases [cAMP]i, and biphasically modified the effect of TSH on cAMP. All of these 5-HT effects were inhibited by 5-HT2 receptor antagonists (spiperone and ketanserin) and by pertussis toxin (PTx), suggesting that the actions of 5-HT are mediated by 5-HT2 receptors, which are coupled to a G protein. This suggestion was supported by the following additional observations: FRTL-5 membranes bound the 5-HT2 agonist, [125I]2,5-dimethoxy-4-iodophenylisopropylamine ([125I]-DOI), and anti-idiotypic antibodies, which recognize 5-HT2 receptors. [125I]-DOI binding was inhibited by guanosine-5'-O-(3-thiotriphosphate) (GTP-gamma-S) and the antibodies were displaced by spiperone. Data are consistent with the hypothesis that 5-HT serves as a PF to F cell messenger.
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PMID:Serotonergic signalling between thyroid cells: protein kinase C and 5-HT2 receptors in the secretion and action of serotonin. 133 23

In UMR-106 osteosarcoma cells we found that PTH activated both the cAMP/protein kinase A and the Ca(2+)-dependent phosphoinositide/protein kinase C (PKC) pathways, but prostaglandin E2 (PGE2) activated only the cAMP pathway. Activation of PKC by the phorbol ester PMA had no effect on cAMP production but enhanced PTH-stimulated cAMP production by 50% or more; the effect on PGE2-induced cAMP was negligible. Inhibition of the alpha-subunit of the inhibitory guanine nucleotide binding protein (Gi) by pertussis toxin pretreatment also enhanced PTH-mediated cAMP production but had no effect on PGE2-induced cAMP production. These results suggest that although PTH-mediated adenylate cyclase activity is regulated via both the stimulatory (Gs) and inhibitory (Gi) guanine nucleotide binding proteins, only Gs regulates PGE2-mediated adenylate cyclase activity in UMR-106 cells. Costimulation with pertussis toxin and PMA did not increase PTH-stimulated cAMP production above that obtained with PMA alone. This implies a similar target of action for pertussis toxin and PMA, that is, the alpha-subunit of Gi. The alpha-subunit of Gi was found to be a substrate for in vitro PKC phosphorylation of membrane fractions from UMR-106 cells, seen as a +/- 40 kD band on SDS-PAGE. Stimulation of in situ 32P-labeled cells with either PMA or PTH also enhanced incorporation of 32P into the 40 kD band. Using the peptide antisera AS/7 and EC/2, we showed that pertussis toxin-labeled subunits of both Gi1 alpha/Gi2 alpha and Gi3 alpha could be immunoprecipitated, respectively, but immunoprecipitation of membrane proteins after in situ phosphorylation and stimulation with PMA precipitated only Gi2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C modulates parathyroid hormone- but not prostaglandin E2-mediated stimulation of cyclic AMP production via the inhibitory guanine nucleotide binding protein in UMR-106 osteosarcoma cells. 133

Phosphoinositide hydrolysis was studied in primary cultures of rat cerebellar astrocytes prelabeled with [3H]myo-inositol. Among the agonists examined, the rank order of efficacies in causing phosphoinositide hydrolysis was bradykinin > endothelin-1 > ATP > norepinephrine. The bradykinin response was robust (24-fold increase) with EC50 value of 30 nM and saturating concentration of 1 microM. Preincubation of cells with pertussis toxin did not affect the activation of phosphoinositide turnover by bradykinin. Although short-term (within 90 min) treatment of cells with phorbol dibutyrate attenuated bradykinin-induced phosphoinositide breakdown, the inhibitory effect was lost after 3-6 h of phorbol dibutyrate treatment. Extended (24 h) preincubation resulted in a potentiation of bradykinin response. Homologous desensitization of bradykinin response was observed in cells prestimulated with bradykinin for up to 6 h. However, similar to the effect of phorbol dibutyrate, 24-h pretreatment with bradykinin selectively sensitized the response to bradykinin. Up-regulation of the bradykinin response was also observed in cells prestimulated with endothelin-1 or norepinephrine for 24 h, although these treatments resulted in only homologous desensitization to their own response. Our results suggest that cultured cerebellar astrocytes express bradykinin receptors coupled to phospholipase C and in these cells protein kinase C plays a more prominent role in the negative-feedback regulation of bradykinin-evoked phosphoinositide response.
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PMID:Regulation of bradykinin-induced phosphoinositide turnover in cultured cerebellar astrocytes: possible role of protein kinase C. 133 44

The alpha 2-C10 adrenergic receptor from human platelets was expressed permanently in Rat-1 fibroblasts. A series of clones that varied in expression of the receptor from 0 to 3.5 pmol/mg of membrane protein were isolated. We have demonstrated recently in cells of one of these clones (1C) that the alpha 2-C10 receptor interacts directly with two distinct pertussis toxin-sensitive G-proteins, Gi2 and Gi3 (Milligan, G., Carr, C., Gould, G. W., Mullaney, I., and Lavan, B.E. (1991) J. Biol. Chem. 266, 6447-6455). High affinity GTPase activity in membranes of cells from the various clones was stimulated by the addition of the alpha 2-adrenergic agonist UK14304, defining that the receptor coupled productively to the G-protein signaling system. Maximal stimulation of high affinity GTPase activity correlated with the levels of receptor expressed. Clones expressing the receptor also demonstrated agonist-mediated inhibition of adenylylcyclase. Futhermore, the alpha 2-C10 receptor in one clone (1C), but not other clones, promoted a marked stimulation in the generation of water-soluble products derived from phosphatidylcholine. The concentration of UK14304 required to produce half-maximal regulation of GTPase activity (20-30 nM), of forskolin-amplified adenylylcyclase activity (30-40 nM), and of choline generation (30-40 nM) were similar. Transphosphatidylation experiments with cells of clone 1C indicated that the receptor-mediated hydrolysis of phosphatidylcholine was via the action of a phospholipase D. All of these effects were attenuated by pretreatment of the cells with pertussis toxin. Dose-effect curves of pertussis toxin-treatment demonstrated similar effective concentrations of the toxin in causing endogenous ADP-ribosylation of both Gi2 and Gi3, inhibition of receptor-stimulated GTPase activity, and phospholipase D activity. Receptor activation of phospholipase D activity was not dependent upon prior phospholipase C-dependent activation of protein kinase C, as alpha 2-adrenergic stimulation of inositol phosphate production was negligible and the presence of the selective protein kinase C inhibitor RO-31-8220, at concentrations up to 10 microM, had no effect on UK14304-mediated production of phosphatidylbutanol. These results demonstrate that expression of the alpha 2-C10 receptor in a heterologous system can result in receptor regulation of signaling elements that appear not to be primary targets for the receptor in vivo. Such results are important in respect to recent observations that transfection of a single defined receptor into separate cell lines can lead to the regulation of distinct effector systems (Vallar, L., Muca, C., Magni, M., Albert, P., Bunzow, J., Meldolesi, J. and Civelli, O. (1990) J. Biol. Chem. 265, 10320-10326).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alpha 2-C10 adrenergic receptors expressed in rat 1 fibroblasts can regulate both adenylylcyclase and phospholipase D-mediated hydrolysis of phosphatidylcholine by interacting with pertussis toxin-sensitive guanine nucleotide-binding proteins. 134 92

In cultured striatal astrocytes, 2-chloroadenosine, an adenosine analog resistant to adenosine deaminase, although inactive alone, markedly potentiated the activation of phospholipase C induced by methoxamine, an alpha 1-adrenergic agonist. This effect was suppressed by antagonists of either A1 adenosine or alpha 1-adrenergic receptors. An influx of calcium and two distinct G-proteins are involved in this phenomenon since the potentiating effect of 2-chloradenosine was suppressed in the absence of external calcium or when cells were pretreated with pertussis toxin. In addition, arachidonic acid is likely involved in this potentiating effect. This was shown first by examining the effects of inhibitors of phospholipase A2 or arachidonic metabolism, then by examining the action of arachidonic acid on the production of inositol phosphates in either the presence or absence of methoxamine, and finally by measuring the release of arachidonic acid. The sequential activation of phospholipase C and of protein kinase C is required for the 2-chloroadenosine-induced activation of phospholipase A2 since 2-chloroadenosine markedly stimulated phospholipase C activity in the absence of methoxamine when protein kinase C was activated by a diacylglycerol analog. Finally, the enhancing effect of 2-chloroadenosine on the methoxamine-evoked response seems to result from an inhibition of glutamate reuptake into astrocytes by arachidonic acid. Indeed, the potentiating effect of 2-chloroadenosine was suppressed when external glutamate was removed enzymatically and mimicked by either selective inhibitors of the glutamate reuptake process or direct application of glutamate.
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PMID:2-Chloroadenosine potentiates the alpha 1-adrenergic activation of phospholipase C through a mechanism involving arachidonic acid and glutamate in striatal astrocytes. 134 73

The mitogenic effect of extracellular ATP on porcine aortic smooth muscle cells (SMC) was examined. Stimulation of [3H]thymidine incorporation by ATP was dose-dependent; the maximal effect was obtained at 100 microM. ATP acted synergistically with insulin, IGF-1, EGF, PDGF, and various other mitogens. Incorporation of [3H]thymidine was correlated with the fraction of [3H]thymidine-labeled nuclei and changes in cell counts. The stimulation of proliferation was also determined by measurement of cellular DNA using bisbenzamide and by following the increase of mitochondrial dehydrogenase protein. The effect of ATP was not due to hydrolysis to adenosine, which shows synergism with ATP. ATP acted as a competence factor. The mitogenic effect of ATP, but not adenosine, was further increased by lysophosphatidate, phosphatidic acid, or norepinephrine. The inhibitor of adenosine deaminase, EHNA, stimulated the effect of adenosine but not ATP. The adenosine receptor antagonist theophylline depressed adenosine-induced mitogenesis. ADP and the non-hydrolyzable analogue adenosine 5'-[beta, gamma-imido]triphosphate (AMP-PNP) were equally mitogenic. Thus extracellular ATP stimulated mitogenesis of SMC via P2Y purinoceptors. The mechanism of ATP acting as a mitogen in SMC was further explored. Extracellular ATP stimulated the release of [3H]arachidonic acid (AA) and prostaglandin E2 (PGE2) into the medium, and enhanced cAMP accumulation in a dose-dependent fashion similar to ATP-induced [3H]thymidine incorporation. Inhibitors of the arachidonic acid metabolism pathway, quinacrine and indomethacin, partially inhibited the mitogenic effect of ATP but not of adenosine. Pertussis toxin inhibited ATP-stimulated DNA synthesis, AA release, PGE2 formation, and cAMP accumulation. Down-regulation of protein kinase C (PKC) by long-term exposure to phorbol dibutyrate (PDBu) partially prevented stimulation of DNA synthesis and activation of the AA pathway by ATP. The PKC inhibitor, staurosporine, antagonized mitogenesis stimulated by ATP. No synergistic effect was found when PDBu and ATP were added together. Therefore, a dual mechanism, including both arachidonic acid metabolism and PKC, is involved in ATP-mediated mitogenesis in SMC. In addition, ATP acted synergistically with angiotensin II, phospholipase C, serotonin, or carbachol to stimulate DNA synthesis. Finally, the possible physiological significance of ATP as a mitogen in SMC was further studied. The effect of endothelin and heparin, which are released from endothelial cells, on ATP-dependent mitogenesis was investigated. Extracellular ATP acted synergistically with endothelin to stimulate a greater extent of [3H]thymidine incorporation than was seen with PDGF plus endothelin. Heparin, believed to have a regulatory role, partially inhibited the stimulation of DNA synthesis caused both by ATP and PDGF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Extracellular ATP and ADP stimulate proliferation of porcine aortic smooth muscle cells. 135 98

The selective alpha 1-adrenergic agonist methoxamine (10(-4)-10(-3) M), in the presence of propranolol (10(-6) M), can reduce both the inwardly rectifying K+ background current (IK1) and the muscarinic cholinergic receptor-activated K+ current (IK,ACh) in rabbit atrial myocytes resulting in action potential prolongation during the final phase of repolarization and a depolarization of the resting membrane potential. The reduction of these K+ currents(s) by alpha 1-adrenoceptor stimulation was insensitive to pre-treatment of atrial myocytes with pertussis toxin (0.15-0.5 micrograms/ml) and was irreversible following intracellular dialysis with the non-hydrolysable guanosine triphosphate (GTP) analogue, Gpp(NH)p (1-5 x 10(-3) M). Neither the protein kinase C (PKC) inhibitors, 1((5-isoquinolinesulphonyl)-2-methylpiperoxine (H-7) (5 x 10(-5) M) and staurosporine (1 x 10(-7) M), nor "downregulation" of PKC by prolonged phorbol ester exposure (5 x 10(-7) M, for 7-8 h) had an effect on the alpha 1-adrenergic modulation of this K+ current. Under cell-attached patch-clamp conditions, bath application of methoxamine reversibly decreased acetylcholine-induced single-channel activity, thus confirming the observed reduction of the ACh-induced current under whole-cell voltage clamp. These results demonstrate that the alpha 1-adrenoceptor, once activated, can reduce current through two different inwardly rectifying K+ channels in rabbit atrial myocytes. These current changes are mediated via a pertussis toxin-insensitive GTP-binding protein, and do not appear to involve the activation of PKC.
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PMID:Activation of alpha 1-adrenoceptors modulates the inwardly rectifying potassium currents of mammalian atrial myocytes. 136 Oct 52

Incubation of the C6 cells with 10 microM idazoxan (an alpha 2-adrenoceptor antagonist and putative antidepressant) for 5 days in vitro resulted in a 23% reduction of beta-adrenoceptor number and a 37% decrease in isoproterenol-induced cyclic AMP accumulation. In contrast, post-receptor stimulated cyclic AMP accumulation (by the use of forskolin or cholera toxin) was unaffected. The desensitization of the beta-adrenoceptor was accompanied by an increase in the KL/KH ratio for this receptor. Chronic in vitro treatment of C6 glioma cells with idazoxan did not significantly affect cholera or pertussis toxin catalyzed ribosylation of Gs and Gi/Go in these cells. Similarly, idazoxan did not alter either the basal levels of protein kinase C (PKC) alpha, or its cytoplasm to membrane translocation. These results suggest that idazoxan may have direct postsynaptic effects, the site of which may be at the level of receptor/G protein interaction.
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PMID:Idazoxan down-regulates beta-adrenoceptors on C6 glioma cells in vitro. 136 12


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