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)

Using cultured cerebral cortical neurons at mature stages (9 days in culture, d.i.c.) it was demonstrated that glutamate, NMDA (N-methyl-D-aspartate) and to a lesser extent KA (kainate) increase the intracellular cGMP concentration ([cGMP]i) whereas no such effect was observed after exposure of the cells to QA (quisqualate) and AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate). No effect of glutamate, NMDA and KA was observed in immature neurons (2 d.i.c.). The pharmacology of these cGMP responses was investigated using the glutamate antagonists APV (2-amino-5-phosphonovalerate) with selectivity for NMDA receptors, CNQX (6-cyano-7-nitro-quinoxaline-2,3-dione) with selectivity for non-NMDA receptors and the novel KA selective antagonists AMOA (2-amino-3-[3-(carboxymethoxy)-5-methylisoxazol-4-yl]propionate) and AMNH (2-amino-3-[2-(3-hydroxy-5-methylisoxazol-4-yl)methyl-5-methyl-3- oxoisoxazolin-4-yl]propionate). In addition, the cytotoxicity of glutamate, NMDA and KA was studied and found to be enhanced by addition of the non-metabolizable cGMP analogue 8-Br-cGMP. On the contrary, the toxicity of QA and AMPA was not affected by 8-Br-cGMP. Pertussis toxin augmented the toxicity elicited by glutamate, NMDA, KA and QA but not that induced by AMPA. On the other hand, only glutamate and KA induced toxicity was potentiated by cholera toxin, which also enhanced the stimulatory effect of glutamate and NMDA but not that of KA on the cellular cGMP content. The toxicity as well as the effects on intracellular cGMP levels could be antagonized by the specific excitatory amino acid (EAA) antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Possible role of cGMP in excitatory amino acid induced cytotoxicity in cultured cerebral cortical neurons. 137 1

The muscarinic stimulation of adenylate cyclase activity in rat olfactory bulb was characterized, with the aim of elucidating the nature of the molecular mechanism involved. Carbachol (CCh) stimulated the enzyme activity in either crude or purified cell membrane preparations and increased cyclic AMP accumulation in miniprisms of olfactory bulb. The CCh stimulation of adenylate cyclase activity displayed a fast onset and was rapidly reversed by addition of atropine. The stimulation was associated with an increase in the apparent Vmax of the enzyme, with no change in the Km for Mg-ATP. The affinity of the enzyme for Mg2+ was enhanced by CCh. The muscarinic effect required GTP at concentrations higher than those needed for enzyme stimulation with either l-isoproterenol or vasoactive intestinal peptide. Moreover, contrary to the beta-adrenergic stimulation, the muscarinic effect disappeared when guanosine 5'-O-(3'-thiotriphosphate) was substituted for GTP. In vivo treatment of olfactory bulbs with pertussis toxin completely prevented the muscarinic stimulation of adenylate cyclase, whereas cholera toxin was without effect. These results indicate that in rat olfactory bulb muscarinic receptors increase adenylate cyclase activity by interacting with a pertussis toxin-sensitive GTP-binding protein different from the stimulatory GTP-binding protein.
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PMID:Properties of muscarinic-stimulated adenylate cyclase activity in rat olfactory bulb. 137 77

The expression of subunits of the guanine nucleotide regulatory protein that mediates hormonal stimulation of adenylyl cyclase (Gs) and of the guanine nucleotide regulatory protein that mediates hormonal inhibition of adenylyl cyclase (Gi) was studied during cell migration and differentiation in the rat small intestine crypt-villus axis. Proliferative crypt cells were separated from nonproliferative mature villus cells and the following data were obtained: 1) alpha s subunits were more abundant in crypt cells than in villus cells as evidenced by cholera toxin-catalyzed [32P]NAD ribosylation and Western blotting of this relative molecular weight (M(r)) 42,000 protein; 2) alpha i2- and alpha i3-subunits (M(r) 40,000 and M(r) 41,000, respectively) were preferentially expressed in villus cells as evidenced by pertussis toxin-catalyzed [32P]NAD ribosylation and Western blotting (alpha i1-subunit was not detectable in intestinal epithelium by using these techniques); 3) Western blotting showed a higher expression of the common beta- (M(r) 36,000) subunit of G proteins in villus cells than in crypt cells; and 4) Northern blot analysis using an alpha s-subunit oligonucleotide probe showed a 1.9-kb mRNA that was more abundant in crypt cells than in villus cells. In contrast, alpha i2- and alpha i3-mRNA species (2.3 and 3.5 kb, respectively), analyzed by using specific cDNA probes, were much more abundant in villus cells than in crypt cells. Finally, two beta-subunit mRNA species of 3.3 and 1.8 kb were detectable in intestinal epithelial cells and were more abundant in villus cells than in crypt cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Gs and Gi protein subunits during cell differentiation in intestinal crypt-villus axis: regulation at the mRNA level. 137 46

It has been proposed that mastoparan (INLKALAALAKKIL) and other mast cell secretagogues such as substance P (SP) or compound 48/80 act by direct activation of the pertussis toxin (PTX)-sensitive G-proteins in intact cells. Here we have investigated whether or not the antagonists of SP, [D-Trp7,9,10] SP1-11 and [D-Trp7,9,10, N-leu11]SP1-11, can similarly induce exocytosis from RINm5F cells. In intact cells mastoparan and the SP antagonists stimulated insulin release in a dose-dependent manner at concentrations ranging from 10 to 100 microM. The maximal effect on insulin release, of both mastoparan and the SP antagonists was comparable to that obtained with 100 microM forskolin. Pretreatment of the intact cells, for 18 h with PTX or 6 h with cholera toxin, did not change the responses induced by both mastoparan and the SP antagonists. This absence of PTX effect, despite the fact that the three PTX substrates at 41, 40 and 39 kDa were ADP ribosylated after pretreatment suggests intrinsic differences between mast and RINm5F cells. Thus the SP antagonists behave similarly to mastoparan in its ability to induce insulin release in RINm5F cells. However, the higher concentrations required with RINm5F cells compared to that needed for mast cells suggest differences either in G-proteins composition or in the phospholipid composition of the membranes.
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PMID:Insulin releasing effects of mastoparan and amphiphilic substance P receptor antagonists on RINm5F insulinoma cells. 137 73

Guanine nucleotide-binding proteins (G proteins) mediate signals between serotonin receptors and adenylate cyclase in Schistosoma mansoni. A bovine Gs alpha cDNA probe was used to isolate a cDNA clone, SG12, encoding the entire alpha-subunit of a G protein of S. mansoni. The cDNA is 1897 base pairs long, contains an open reading frame of 1137 base pairs, and codes for a deduced protein of 379 amino acids. The putative protein encoded by the clone has an exact amino acid match with bovine Gs alpha of 65% and a 78% match when conserved amino acid substitutions are considered. In contrast, the exact and conserved matches of the schistosome alpha-subunit with bovine Gi are 41 and 61%, respectively. A comparison of the deduced amino acid sequence of SG12 with a variety of different G alpha proteins indicates that all the major structural features characteristic of a Gs alpha protein are present in the S. mansoni gene. The schistosome clone contains the putative site for ADP-ribosylation by cholera toxin found in Gs alpha but does not contain the ADP-ribosylation site for pertussis toxin present in Gi alpha. The amino acids are completely conserved at the GTP-binding sites. On a Northern blot, the cDNA hybridizes to a major band of 3.1 kilobases in RNA from adult schistosomes. The message appears to be absent in miracidia and cercariae, but a faint 3.1-kilobase band is visible in the early schistosomule stage preceding adulthood. This evidence, when added to previous biochemical data, indicates that the expression of this gene is developmentally controlled.
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PMID:Cloning and characterization of a cDNA coding for the alpha-subunit of a stimulatory G protein from Schistosoma mansoni. 137 44

Fully-differentiated mouse 3T3-L1 fibroblasts accumulate large amounts of lipid at 7-10 days after induction by insulin or by dexamethasone and a methyl xanthine. G proteins mediate transmembrane signalling from a diverse group of cell-surface receptors to effector units that include phospholipase C, adenylyl cyclase and ion channels. They are also targets of regulation themselves. 3T3-L1 fibroblasts display marked changes in levels of G protein when induced to differentiate to adipocytes. Here we show that cholera toxin, which ADP-ribosylates and activates the G protein subunit Gs alpha, blocks the induction of differentiation, whereas increasing intracellular cyclic AMP directly with the dibutyryl analogue or indirectly with pertussis toxin or forskolin does not affect differentiation. Oligodeoxynucleotides antisense to the sequence encoding Gs alpha accelerate differentiation markedly. The time course of adipogenesis declined from 7-10 days in controls to roughly 3 days in cultures treated with antisense-Gs alpha oligodeoxynucleotides, whereas oligodeoxynucleotides, antisense to Gi alpha 1, Gi alpha 3, and sense and missense to Gs alpha, had no such effect. Antisense-Gs alpha alone induced differentiation by day 7, indicating that Gs alpha activity modulates differentiation in 3T3-L1 cells, acting in a new role which is independent of increased intracellular cAMP.
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PMID:Antisense oligodeoxynucleotides to GS protein alpha-subunit sequence accelerate differentiation of fibroblasts to adipocytes. 137 45

Transforming growth factor-beta 1 (TGF-beta 1) regulates the expression of the carcinoembryonic antigen (CEA) gene family in the human colon carcinoma cell line Moser. The mechanisms through which it acts, however, are unknown. In this communication, several lines of evidence are presented to show that the induction of CEA expression and secretion (collectively called CEA responses) by TGF-beta 1 is associated with protein kinase C (PKC) pathway of signal transduction. Treatment of intact cells with the PKC-specific inhibitor calphostin C down-modulated cellular PKC phosphotransferase activity and blocked the induction of the CEA responses by TGF-beta 1. Depletion of PKC by treatment of intact cells with phorbol ester also blocked the action of TGF-beta 1. The induction of the CEA responses by TGF-beta 1 was also blocked by the protein kinase inhibitor 1-(isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), which also inhibited cellular PKC activity. However, TGF-beta 1 did induce the CEA responses in intact cells treated with the calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7), the calmodulin-dependent phosphodiesterase inhibitor calmidazolium, the diacylglycerol kinase inhibitor R59 022, and the G-protein inhibitors cholera toxin and pertussis toxin. Treatment of intact cells with TGF-beta 1 induced a rapid and transient increase in PKC phosphotransferase activity. TGF-beta 1, however, was unable to induce PKC enzymatic activity in cells pretreated with calphostin C. Therefore, it is concluded that TGF-beta 1 regulates the CEA responses through a signal transducing pathway associated with PKC.
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PMID:Role of protein kinase C in transforming growth factor-beta 1 induction of carcinoembryonic antigen in human colon carcinoma cells. 138 May 12

Regulation of phosphate uptake by the blood-brain barrier was studied in isolated bovine capillaries. Dibutyryl cAMP, in the presence of 3-isobutylmethylxanthine, resulted in a dose-dependent inhibition of phosphate uptake. Phosphate influx, with or without 3-isobutylmethylxanthine, was not different. Inhibition of phosphate uptake was also observed when capillaries were preincubated with isoproterenol, parathyroid hormone, insulin and acidic or basic fibroblast growth factors. Treatment of capillaries with vasoactive intestinal peptide, prostaglandin E1, angiotensin II, epidermal growth factor and phorbol esters did not affect phosphate transport. Endothelin I increased phosphate uptake by 15%. Preincubation with cholera toxin also resulted in a dose-dependent decrease in phosphate uptake. In addition, pertussis toxin inhibited phosphate transport by 29%, but only in the presence of 3-isobutylmethylxanthine. These results demonstrate that generation of second messengers, following receptor stimulation, can induce physiological effects on capillary phosphate influx and suggest that G proteins may modulate this transport.
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PMID:Regulation of phosphate transport by second messengers in capillaries of the blood-brain barrier. 138 98

The present studies were conducted to characterize the specific binding of recombinant human [125I]acidic fibroblast growth factor ([125]aFGF) to the cloned human fibroblast growth factor (FGF) receptor, flg, overexpressed on stably transfected NIH 3T3 mouse fibroblast (NFlg26) cell membranes. In the presence of 5 U/ml of heparin to block [125I]aFGF binding to membrane bound heparan sulfate proteoglycans, specific [125I]aFGF binding was optimal in the presence of 0.2 M NaCl and in a pH range of 7 to 9. [125I]aFGF labeled a single class of recognition sites with high affinity (Kd = 0.27 nM) and limited capacity (apparent maximum binding = 19.5 pmol/mg of protein). A similar estimate of ligand affinity (Kd = 0.25 nM) was determined from association and dissociation rate experiments. aFGF, basic fibroblast growth factor and several glycine-substituted point mutations of aFGF potently inhibited 0.1 nM [125I]aFGF binding. A variety of putative FGF receptor ligands including poly-L-lysines and poly-L-arginines, protamine, suramin and wheat germ agglutinin were shown to have weak or no affinity for the [125I]aFGF recognition site. Additional saturation studies, conducted in the presence of a lower (0.1 U/ml) heparin concentration, indicated that [125I] aFGF labeled both the high affinity (Kd = 0.02 nM) FGF-flg receptor and a separate class of lower affinity (Kd = 2 nM) recognition sites. Pretreatment of NFlg26 cell membranes with pertussis toxin resulted in a heparin-dependent decrease in the binding affinity (Kd values of 0.57-1.15 nM) of [125I]aFGF. Similar pretreatment with cholera toxin did not significantly affect [125I] aFGF binding. Guanine nucleotides were also found to significantly reduce 0.1 nM [125I]aFGF binding in a heparin-dependent fashion. The present data demonstrate that, in the presence of heparin, [125I]aFGF binds with high affinity to the cloned FGF-flg receptor on NFlg26 cell membranes. However, at a low heparin concentration (0.1 U/ml), [125I]aFGF binds to the FGF-flg receptor with higher affinity than was observed in the presence of 5 U/ml of heparin, and also binds a class of lower affinity recognition sites which are consistent with the labeling of cell surface heparan sulfate proteoglycans. The present data also indicate that agents which are known to interfere with receptor/G-protein coupling reduce the binding affinity of [125I]aFGF and suggest that the FGF-flg receptor may be coupled to a G-protein in addition to its intrinsic tyrosine kinase activity.
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PMID:Characterization of [125I]acidic fibroblast growth factor binding to the cloned human fibroblast growth factor receptor, FGF-flg, on NIH 3T3 cell membranes: inhibitory effects of heparin, pertussis toxin and guanine nucleotides. 138 94

The N-methyl-D-aspartate (NMDA)-sensitive subtype of glutamate receptor, which gates Ca(2+)-permeable ion channels, is known for its role in learning and memory formation, in the induction of long-term potentiation, and also in seizure activity and neurotoxicity. In primary cultures of cerebellar neurons, agonists of NMDA receptors induce a dose-dependent release of [3H]arachidonic acid ([3H]AA), which is potentiated by activation of the glycine-positive modulatory site and inhibited by NMDA receptor antagonists. NMDA receptor-induced [3H]AA release is inhibited by quinacrine and partially depends on the presence of extracellular calcium. The [3H]AA release is not sensitive, however, to pretreatment with pertussis or cholera toxin, which suggests a Ca(2+)-dependent activation of phospholipase A2 not employing G proteins. Pretreatment of cultures with the natural and semisynthetic sphingolipids GT1b and PKS 3, respectively, inhibits NMDA receptor-mediated [3H]AA release. We also demonstrated glutamate-evoked [3H]AA release from rat hippocampal slices, which is NMDA receptor mediated, calcium dependent and sensitive to quinacrine. Arachidonic acid and its metabolites have been shown to play a role as second messengers and to modulate neuronal activity. Moreover, they are thought to act as transsynaptic modulators in the mechanism of NMDA receptor-induced long-term potentiation in the hippocampus. Their role in ischemic brain pathology has also been postulated. Our experiments on cultured cerebellar granule cells, incubated in a Mg(2+)-free medium deprived of glucose and oxygen, demonstrated a time-dependent stimulation of [3H]AA release. This release was inhibited by antagonists of NMDA receptors and by quinacrine. Stimulation of NMDA-sensitive glutamate receptors and the subsequent calcium-mediated activation of phospholipase A2 may play a role in the in vivo release of arachidonic acid during brain ischemia. This hypothesis is supported by the observation that the enhanced level of thromboxane B2 in the gerbil brain after 5 min of global ischemia is reduced by the systemic application of either the NMDA antagonist MK-801 or the ganglioside GM1.
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PMID:NMDA receptor-mediated arachidonic acid release in neurons: role in signal transduction and pathological aspects. 138 78


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