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)

We previously demonstrated that 5-hydroxytryptamine (5-HT) enhances the cationic current activated by extracellular ATP in rat pheochromocytoma PC12 cells. We report here that pertussis toxin (PTX) modulates this 5-HT-dependent enhancement in these cells. 5-HT potentiated ATP-evoked intracellular Ca2+ concentration ([Ca]i) rise and dopamine release over a concentration range from 1 to 100 microM. When cells were pre-treated with PTX, this potentiation was accentuated. Pretreatment with PTX also accentuated the 5-HT-dependent enhancement of the ATP-activated current. These results suggest that the enhancement by 5-HT of the ATP-evoked responses is negatively regulated by a mechanism mediated through PTX-sensitive GTP-binding protein.
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PMID:Accentuation by pertussis toxin of the 5-hydroxytryptamine-induced potentiation of ATP-evoked responses in rat pheochromocytoma cells. 774 65

Among subfamilies of G-protein-coupled receptors, agonists initiate several cell signaling events depending on the receptor subtype (R) and the type of G-protein (G) or effector molecule (E) expressed in a particular cell. Determinants of signaling specificity/efficiency may operate at the R-G interface, where events are influenced by cell architecture or accessory proteins found in the receptor's microenvironment. This issue was addressed by characterizing signal transfer from R to G following stable expression of the alpha 2A/D adrenergic receptor in two different membrane environments (NIH-3T3 fibroblasts and the pheochromocytoma cell line, PC-12). Receptor coupling to endogenous G-proteins in both cell types was eliminated by pertussis toxin pretreatment and R-G signal transfer restored by reconstitution of cell membranes with purified brain G-protein. Thus, the receptor has access to the same population of G-proteins in the two different environments. In this signal restoration assay, agonist-induced activation of G was 3-9-fold greater in PC-12 as compared with NIH-3T3 alpha 2-adrenergic receptor transfectants. The cell-specific differences in signal transfer were observed over a range of receptor densities or G-protein concentration. The augmented signal transfer in PC-12 versus NIH-3T3 transfectants occurred despite a 2-3-fold lower level of receptors existing in the R-G-coupled state (high affinity, guanyl-5'-yl imidodiphosphate-sensitive agonist binding), suggesting the existence of other membrane factors that influence the nucleotide binding behavior of G-protein in the two cell types. Detergent extraction of PC-12 but not NIH-3T3 membranes yielded a heat-sensitive, macromolecular entity that increased 35S-labeled guanosine 5'-O-(thiotriphosphate) binding to brain G-protein in a concentration-dependent manner. These data indicate that the transfer of signal from R to G is regulated by a cell type-specific, membrane-associated protein that enhances the agonist-induced activation of G.
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PMID:Factors determining specificity of signal transduction by G-protein-coupled receptors. Regulation of signal transfer from receptor to G-protein. 779 13

1. The amphiphilic peptide mastoparan is known to affect phosphoinositide breakdown, calcium influx, and exocytosis of hormones and neurotransmitters and to stimulate the GTPase activity of guanine nucleotide-binding regulatory proteins. Another amphiphilic peptide, adenoregulin was recently identified based on stimulation of agonist binding to A1-adenosine receptors. 2. A comparison of the effects of mastoparan and adenoregulin reveals that these peptides share many properties. Both stimulate binding of agonists to receptors and binding of GTP gamma S to G proteins in brain membranes. The enhanced guanyl nucleotide exchange may be responsible for the complete conversion of receptors to a high-affinity state, complexed with guanyl nucleotide-free G proteins. 3. Both peptides increase phosphoinositide breakdown in NIH 3T3 fibroblasts. Pertussis toxin partially inhibits the phosphoinositide breakdown elicited by mastoparan but has no effect on the response to adenoregulin. N-Ethylmaleimide inhibits the response to both peptides. 4. In permeabilized 3T3 cells, both adenoregulin and mastoparan inhibit GTP gamma S-stimulated phosphoinositide breakdown. Mastoparan slightly increases basal cyclic AMP levels in cultured cells, followed at higher concentrations by an inhibition, while adenoregulin has minimal effects. 5. Both peptides increase calcium influx in cultured cells and release of norepinephrine in pheochromocytoma PC12 cells. The calcium influx elicited by the peptides in 3T3 cells is not markedly altered by N-ethylmaleimide. 6. Multiple sites of action appear likely to underlie the effects of mastoparan/adenoregulin on receptors, G proteins, phospholipase C, and calcium.
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PMID:Effects of the amphiphilic peptides mastoparan and adenoregulin on receptor binding, G proteins, phosphoinositide breakdown, cyclic AMP generation, and calcium influx. 784 73

The Deleted in Colorectal Cancer (DCC) gene is a candidate tumor suppressor gene that is predicted to encode a transmembrane polypeptide with strong similarity to the neural cell adhesion molecule (N-CAM) family. Previous studies have suggested that several different N-CAMs, when expressed in non-neuronal cell types can stimulate neurite outgrowth from PC12 rat pheochromocytoma cells. Based on the predicted structural similarity of DCC to N-CAMs, we sought to determine whether NIH3T3 cells expressing DCC could stimulate neurite outgrowth in PC12 cells. We found that NIH3T3 cell lines expressing DCC could stimulate PC12 cells to extend neurites. Supernatants from DCC-transfected NIH3T3 cells did not induce neurite outgrowth above background levels, suggesting that cell-cell interaction was required. NIH3T3 cells expressing a truncated form of DCC, lacking the majority of the cytoplasmic domain sequences, also failed to induce neurite outgrowth above the levels seen with control NIH3T3 cells, suggesting that the cytoplasmic domain of DCC was necessary for its neurite-promoting function. In contrast to NGF-mediated neurite outgrowth, the DCC-mediated response was inhibited by treatment with pertussis toxin or the combination of N- and L-type calcium channel blockers, and was unaffected by the transcriptional inhibitor cordycepin. The data suggest that the DCC protein can function in a fashion analogous to other N-CAMs to alter PC12 cell phenotype through intracellular pathways distinct from those involved in NGF signaling.
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PMID:NIH3T3 cells expressing the deleted in colorectal cancer tumor suppressor gene product stimulate neurite outgrowth in rat PC12 pheochromocytoma cells. 813 5

We have investigated the role of endothelin-3 (ET-3) in the stimulus-secretion coupling mechanism in rat pheochromocytoma PC12 cells. ET-3 (10-100 nM) evoked both dopamine (DA) release and an increase in intracellular Ca2+ concentration ([Ca]i). The ET-3-evoked DA release was partially inhibited by pretreatment with pertussis toxin (PTX; 2 ng/ml, 20 h). The release was also attenuated by the voltage-gated Ca channel (VGC) blockers Cd2+ (300 microM) or nicardipine (30 microM) and was completely abolished when external Ca2+ was removed. ET-3-evoked [Ca]i increase was attenuated by the application of these VGC blockers and by pretreatment with PTX, and was abolished by removal of extracellular Ca2+. Removal of external Na+ had no effect on either response. In light of these findings, we conclude that ET-3 evokes both DA release and an increase in [Ca]i by a mechanism which involves the activation of PTX-sensitive VGCs and the resultant influx of Ca2+.
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PMID:Endothelin-3 activates a voltage-gated Ca channel via a pertussis toxin sensitive mechanism leading to dopamine release from PC12 cells. 817 98

There are two major isoforms of the angiotensin II receptor, type 1 (AT1) and type 2 (AT2). AT2 is distinguished from AT1 with respect to its ligand selectivity, its insensitivity to non-hydrolyzable GTP analogues, and its as yet unidentified biological functions. In the present study we have expression-cloned AT2 cDNA from a cDNA library of a rat pheochromocytoma cell line (PC12w). Rat AT2 cDNA encodes a 363-amino acid protein that has seven transmembrane domains. AT1 is the closest in homology to AT2 but with only a 32% identity of amino acid sequence. Stably expressed in COS-7 cells, the receptor showed selective binding to AT2-specific ligands PD123319 and CGP42112A but not to the AT1-specific ligand, losartan. Northern blot analysis revealed that the mRNA of rat AT2 was expressed not only in PC12w cells but also in the adrenal glands and in the inferior olive of the brain, both of which are known to contain AT2 type binding sites. The expressed AT2 receptor mediated angiotensin II-induced inhibition of protein tyrosine phosphatase, an action that was dependent on a pertussis toxin-sensitive G-protein-coupled mechanism in COS-7 cells. The AT2-specific ligand CGP42112A was an agonist rather than antagonist in the inhibition of phosphotyrosine phosphatase. AT2 did not cause a decrease in cGMP in PC12w or COS-7 cells expressing AT2 stably. These results indicate that the AT2 receptor is structurally and functionally different from AT1 and suggest novel functional roles of the renin-angiotensin system in cross-talk with phosphotyrosine signaling by modulating protein phosphotyrosine levels.
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PMID:Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. 822 11

In rat PC12 pheochromocytoma cells, extracellular ATP stimulated 45Ca2+ influx even in the presence of nifedipine, a Ca2+ antagonist that inhibits the voltage-dependent L-type Ca2+ channel, and stimulated the formation of inositol trisphosphate (IP3). The effect of ATP on 45Ca2+ influx was more potent than that on the formation of IP3 at a dose lower than 0.1 mM. 12-O-Tetradecanoylphorbol-13-acetate, a protein kinase-C (PKC)-activating phorbol ester, which by itself had little effect on 45Ca2+ influx, significantly reduced the ATP-induced 45Ca2+ influx in a dose-dependent manner in the range between 1 nM and 0.1 microM. However, 4 alpha-phorbol 12, 13-didecanoate, a PKC-nonactivating phorbol ester, had little effect on the 45Ca2+ influx induced by ATP. Staurosporine, an inhibitor for PKC, significantly enhanced the ATP-induced 45Ca2+ influx. Pertussis toxin inhibited the ATP-induced formation of IP3 in a dose-dependent manner in the range between 0.1 ng/ml and 1 microgram/ml. On the other hand, pertussis toxin significantly enhanced the ATP-induced 45Ca2+ influx. These results strongly suggest that extracellular ATP-induced Ca2+ influx is autoregulated due to the activation of PKC resulting from pertussis toxin-sensitive GTP-binding protein-coupled phosphoinositide hydrolysis in PC12 pheochromocytoma cells.
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PMID:Cross-talk between Ca2+ influx and phosphoinositide hydrolysis by extracellular adenosine triphosphate in rat PC12 pheochromocytoma cells. 839 21

The influence of activation of protein kinase C (PKC) and cyclic AMP on noradrenaline (NA) release in the neurosecretory rat pheochromocytoma PC12 cell line was investigated. External ATP induced [3H]NA release from prelabeled PC12 cells, in the presence of extracellular CaCl2. The potency order of ATP analogs was adenosine 5'-O-(gamma-thiotriphosphate) > or = ATP > 2-methylthio ATP > 2',3'-O-(4-benzoyl)benzoyl ATP. alpha,beta-Methylene ATP, beta gamma-methylene ATP, and 8-bromo ATP were inactive. Neither ADP, GTP, nor ITP was active. The addition of phorbol 12-myristate 13-acetate (PMA) or agents elevating the cyclic AMP content, such as vasoactive intestinal peptide (VIP) or an adenosine analog, also stimulated [3H]NA release. Not only high K(+)- but also ATP-stimulated [3H]NA release was enhanced by co-addition with PMA or agents elevating the cyclic AMP content. PMA and VIP had no effect on the cytosolic free Ca2+ concentration ([Ca2+]i) or on the ATP-stimulated [Ca2+]i rise, although both stimulatory effects on [3H]NA release were dependent on extracellular CaCl2. The addition of PMA stimulated [3H]NA release dose-dependently, and enhanced 300 microM (maximal dose) ATP-stimulated [3H]NA release without changing the affinity for ATP. The effect of PMA was inhibited by PKC inhibitors such as calphostin C and in PKC-depleted cells, and potentiated by elevation of cyclic AMP. These data suggest that the process of ATP-stimulated NA release, not ATP-stimulated Ca2+ influx, is regulated by the dual, PKC- and cyclic AMP-dependent mechanisms, positively and independently. Treatment with pertussis toxin had no effect on the ATP-stimulated [Ca2+]i rise or [3H]NA release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of protein kinase C and A activation on ATP-stimulated release of [3H]noradrenaline from PC12 cells. 854 66

The roles of G(o), a heterotrimeric GTP binding (G) protein with a 40-kDa alpha subunit and which is localized predominantly in neuronal cells, in exocytosis have been discussed recently. PC12 pheochromocytoma cell line is a convenient model in which to study the Ca(2+)-dependent mechanisms of the neurosecretory process. The stimulation of ATP receptors or addition of KCl stimulated an elevation of cytosolic free Ca2+ concentration ([Ca2+]i) and [3H]noradrenaline (NA) release in PC12 cells. In this study, we investigated the roles of G(o) in ATP- and KCl-stimulated reactions. Nerve growth factor treatment for 2 days and transfection of PC12 cells with cDNA of subunit of (G(o alpha) had no effect on ATP-stimulated [3H]NA release, although both treatments increased levels of the G(o alpha) and its trimeric form by about twofold over those in unstimulated cells. The [Ca2+]i rise induced by ATP in NGF-treated cells was similar to that in control cells, although the maximal response was slightly smaller. Cholera toxin treatment for 2 days inhibited ATP- and KCl-stimulated NA release, although this treatment caused an approximately twofold increase in the level of G(o). Pertussis toxin treatment, which ADP ribosylated over 90% of endogenous G proteins such as G(o), had no effect on ATP-stimulated reactions. These findings show that G(o) does not directly regulate ATP-stimulated Ca2+ channels or the NA release process in PC12 cells. Cholera toxin-sensitive protein(s) may regulate exocytosis.
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PMID:G(o) protein does not regulate ATP-stimulated [Ca2+]i elevation or noradrenaline release in PC12 cells. 880 2

In PC12 rat pheochromocytoma cells differentiated with nerve growth factor (NGF), neuropeptide Y inhibited depolarization-stimulated catecholamine synthesis as determined by in situ measurement of 3,4-dihydroxyphenylalanine (DOPA) production in the presence of the decarboxylase inhibitor m-hydroxybenzylhydrazine (NSD-1015). The inhibition by neuropeptide Y was concentration-dependent and was prevented by pretreatment with pertussis toxin, suggesting the involvement of a GTP-binding protein of the Gi or Go subtype. The neuropeptide Y analog [Leu31,Pro34]neuropeptide Y also caused inhibition of DOPA production, but was less potent than neuropeptide Y itself, while peptide YY and neuropeptide Y-(13-36) had no significant effect. This pattern is most consistent with the involvement of the neuropeptide Y Y3 receptor subtype. In PC12 cells differentiated with dexamethasone, neuropeptide Y also caused a concentration-dependent inhibition of DOPA production, while peptide YY was again without effect. Neuropeptide Y had no effect on DOPA production in undifferentiated PC12 cells. These results indicate that neuropeptide Y can modulate catecholamine synthesis in addition to its modulatory effects on catecholamine release.
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PMID:Neuropeptide Y inhibits depolarization-stimulated catecholamine synthesis in rat pheochromocytoma cells. 899 1


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