Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress appears to contribute to neuronal dysfunction in a number of neurodegenerative conditions, notably including Alzheimer's disease, in which cholinergic receptor-linked signal transduction activity is severely impaired. To test whether oxidative stress could contribute to deficits in cholinergic signaling, responses to carbachol were measured in human neuroblastoma SH-SY5Y cells exposed to H2O2. DNA binding activities of two transcription factors that are respondent to oxidative conditions, AP-1 and NF kappa B, were measured in nuclear extracts. H2O2 and carbachol individually induced dose- and time-dependent increases in AP-1 and NF kappa B. In contrast, when given together, H2O2 concentration dependently (30-300 microM) inhibited the increase after carbachol in AP-1. Carbachol's stimulation of NF kappa B was not inhibited except with a high concentration (300 microM) of H2O2, which was associated with impaired activation of protein kinase C. Lower concentrations of H2O2 (30-300 microM) inhibited carbachol-induced [3H]phosphoinositide hydrolysis, and this inhibition correlated (r = 0.95) with the inhibition of carbachol-induced AP-1. Activation [3H]phosphoinositide hydrolysis by the calcium ionophore ionomycin was unaffected by H2O2, indicating that phospholipase C and phosphoinositides were impervious to this treatment. In contrast, activation with NaF of G-proteins coupled to phospholipase C was concentration dependently inhibited by H2O2, indicating impaired G-protein function. These effects of H2O2 are similar to signaling impairments reported in Alzheimer's disease brain, which involve deficits in receptor- and G-protein-stimulated phosphoinositide hydrolysis, but not phospholipase C activity. Thus, these findings indicate that oxidative stress may contribute to impaired phosphoinositide signaling in neurological disorders in which oxidative stress occurs, and that oxidative stress can differentially influence transcription factors activated by cholinergic stimulation.
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PMID:Cholinergic stimulation of AP-1 and NF kappa B transcription factors is differentially sensitive to oxidative stress in SH-SY5Y neuroblastoma: relationship to phosphoinositide hydrolysis. 881 74

G protein-coupled receptors activate phospholipase C (PLC)-beta isoforms by the alpha or beta gamma subunits of G proteins, whereas growth-factor receptors activate PLC-gamma isoforms by phosphorylating tyrosine residues of the enzyme. As a common substrate for PLC enzymes, phosphatidylinositol 4,5-bisphosphate [Ptdins(4,5)P2] may play a pivotal role in the regulation of cellular PLC activity. Because small-molecular-weight G proteins have been implicated in the synthesis of Ptdins(4,5)P2, we studied the effect of Clostridium difficile toxin B, which glucosylates and thereby inactivates small G proteins of the Rho family, on receptor-stimulated PLC activity. We report here that in N1E-115 neuroblastoma cells, stimulation of inositol phosphate formation by the G protein-coupled receptor agonists bradykinin and lysophosphatidic acid and by the tyrosine kinase receptor agonist platelet-derived growth factor is largely attenuated by toxin B treatment. Furthermore, inositol phosphate production stimulated by the stable GTP analog guanosine 5'-O-(3-thio)-triphosphate in permeabilized N1E-115 cells was inhibited by C3 exoenzyme, which specifically inactivates Rho proteins. The inhibition by toxin B was apparently not caused by its effect on the cytoskeleton. In addition, the level of platelet-derived growth factor receptors, which was studied with immunoblotting, was unaffected by toxin B. Using exogenous Ptdlns(4,5)P2 as PLC substrate, it was found that the intrinsic enzymatic activity of PLC activated either by Ca2+ or by guanosine 5'-O-(3-thio)triphosphate was not altered by toxin B. However, toxin B decreased strongly, by up to 80%, the cellular level of Ptdins(4,5)P2 in a concentration-dependent manner, without changing those of phosphatidylinositol and phosphatidylinositol 4-phosphate. These results, together with the recent finding that Rho family proteins can regulate phosphatidylinositol 4-phosphate 5-kinase activity, demonstrate that Rho proteins are presumably important regulators of Ptdins(4,5)P2 synthesis and, thereby, play an integral role in the regulation of cellular signaling by PLC enzymes.
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PMID:Inhibition by toxin B of inositol phosphate formation induced by G protein-coupled and tyrosine kinase receptors in N1E-115 neuroblastoma cells: involvement of Rho proteins. 886 31

Lithium has a biphasic effect of the agonist-dependent accumulation of Ins(1,4,5)P3 in human neuroblastoma SH-SY5Y cells. These effects consist of a transient reduction, followed by a long-lasting increase in Ins(1,4,5)P3 as compared to controls. The Li+ effects are dose dependent, and were observed at concentrations used in the treatment of bipolar disorders, and thus may have therapeutic implications. The mechanism of the Li+ effect on Ins(1,4,5)P3 accumulation requires further investigation. The transient reduction of Ins(1,4,5)P3 was observed under conditions where Li+ causes only a moderate increase in the inositol mono- and bi-phosphates. Supplementation with exogenous inositol had no effect on the level of Ins(1,4,5)P3, indicating that the mechanism of the Li(+)-dependent reduction of Ins(1,4,5)P3 is not due to inositol depletion. Li+ did not interfere with degradation of Ins(1,4,5)P3 after receptor-blockage with atropine, suggesting that Li+ has no direct effect on the Ins(1,4,5)P3 metabolizing enzymes. A direct effect of Li+ on the phospholipase C is also unlikely. Entry of Ca2+ into the cells is an important factor, which affects agonist-stimulated accumulation of Ins(1,4,5)P3, as well as absolute values of Li(+)-dependent increase in Ins(1,4,5)P3; however, it is not essential for the manifestation of Li+ effects. Our results also show that manifestation of Li+ effects in human neuroblastoma cells requires the stimulation of muscarinic receptors and activation of PLCs, PKCs, and/or that other staurosporine/H-7/GF 109203X-sensitive protein kinases are involved in the regulation of Ins(1,4,5)P3 during the plateau phase of ACh-stimulation. We also suggest an important role for these enzymes in the Li(+)-dependent elevation of Ins(1,4,5)P3.
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PMID:Phosphoinositide signalling in human neuroblastoma cells: biphasic effect of Li+ on the level of the inositolphosphate second messengers. 886 50

The pungent sesquiterpenoid unsaturated dialdehydes polygodial and isovelleral, have previously been shown to increase the intracellular free calcium concentration [Ca2+]i in human neuroblastoma SH-SY5Y cells, partly by a release from intracellular Ca2+ stores, whereas the non-pungent compound epipolygodial, had no effect on the [Ca2+]i. In this study, we investigated the effect of isovelleral, polygodial and epipolygodial on inositol phosphate (IP) formation on the assumption that there might be a correlation between the release of intracellular Ca2+ and pungency of the compounds. It was found that polygodial induced IP mobilization in a concentration dependent way, whereas isovelleral had no effect on the IP formation in the SH-SY5Y cells. Phosphoinositide (PPI) turnover was activated by epipolygodial, but only at concentrations 40-fold higher than for polygodial, which emphasizes the importance of the correct stereometry in the dialdehyde configuration for the biological activity of polygodial. The polygodial-induced formation of IP1 was reduced by 71% under extracellular calcium-free conditions, which suggests feedback interactions between the IP formation and the increase in [Ca2+]i to account for a periodic activation of phospholipase C(PLC).
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PMID:Polygodial induces inositol phosphate turnover in human neuroblastoma SH-SY5Y cells. 890 37

Neuroblastoma x glioma hybrid NG 108-15 and neuroblastoma x fibroblast hybrid NL308 cells possess endogenous bradykinin B2 receptors and m4 muscarinic acetylcholine receptors (mAChRs), which couple to phospholipase C and adenylate cyclase, respectively. Four genetic subtypes of mAChRs differed in their effects when stimulated in NG108-15 and NL308 cells overexpressing mAChRs. Broadly speaking, the principal effects fell into two categories: the odd-numbered receptors (m1 and m3) activated phospholipase C and increased inositol trisphosphate/Ca2+, as bradykinin did, whereas the even-numbered receptors (m2 and m4) inhibited adenylate cyclase via a pertussis toxin (PTx)-sensitive G-protein in NG108-15 cells. But all four types of NL308 cells overexpressing each m1, m2, m3 and m4 receptor activated phospholipase C, while keeping the PTx-sensitivity in m2/m4, but not in m1/m3 receptors. Coupling to ion channel effectors showed a comparable dichotomy in NG108-15 cells, while cross-activation occurred in NL308 cells.
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PMID:Inositol trisphosphate/Ca2+ as messengers of bradykinin B2 and muscarinic acetylcholine m1-m4 receptors in neuroblastoma-derived hybrid cells. 890 60

Multiple cellular responses are regulated through the generation of lipid second messengers upon activation of phospholipases. One such response concerns the activity of a class of kinase constituting the protein kinase C family. The production of specific molecular species of lipid second messengers may be therefore of prime importance in the activation of a member of the PKC isoforms. Prompted by this possibility we investigated the production of 1,2 diacyl-sn-glycerol (DAG) and phosphatidic acid (PtdOH) in LA-N-1 neuroblastoma cells under various physiological states. 12-0-Tetradecanoylphorbol 13-acetate (TPA) stimulation activated a phospholipase D (PLD) specific for phosphatidylcholine (PtdCho) in proliferating cells and a phospholipase C (PLC) specific for phosphatidylethanolamine (PtdEtn) in retinoic acid (RA) differentiated cells. These separate activations produced different molecular species of DAG or PtdOH. PtdOH was able to stimulate the Ca2+ dependent protein kinase C (PKC) by a mechanism which differed from the action of DAG. PtdOH did not induce the translocation of the PKC to the membrane. Moreover PtdOH, in contrast to DAG, prevented PKC degradation by inhibiting the enzymatic hydrolysis by m-calpain. These observations suggest that the stimulation of cells by agonists elicited the production of specific molecular species of lipid second messengers depending on the physiological status of the cells, and probably on the nature of the stimulus. It seems therefore likely that the generation of specific lipid second messengers may activate specific PKC isoforms resulting in a specific cellular response.
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PMID:Production and function of lipid second messengers in proliferating and differentiated neuroblastoma cells. 890 81

Mas-7, a mastoparan derivative, induces elevation of intracellular free Ca2+ concentration ([Ca2+]i) along two independent pathways. The minor contribution occurs via phospholipase C activation and is negatively regulated by treatment with phorbol 12-myristate 13-acetate, a protein kinase C activator. The major contribution involves plasma membrane pores allowing not only Ca2+, Mn2+, and Na+ to enter but also the uptake of ethidium bromide (314 Da) and lucifer yellow (457 Da), but not fura-2 (831 Da), Evans blue (961 Da), and fluorescein-conjugate phalloidin (1,175 Da). Mas-7-induced current, as measured in planar lipid bilayers, reveals that Mas-7-induced pores have two slope conductances, 290 and 94 pS, and that the pores are nonselective for cations. The results also indicate that Mas-7 can produce pores by direct interaction with the plasma membrane without the involvement of membrane proteins and cytosolic factors. Besides in human neuroblastoma cells, similar Mas-7 effects were also observed in other cell lines such as HL-60, 1321N1 human astrocytoma, and bovine chromaffin cells. The data suggest that the Mas-7-induced [Ca2+]i elevation is the combined result of Ca2+ release from stores via phosphoinositide turnover and prolonged Ca2+ influx through membrane pores.
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PMID:Induction of cytosolic Ca2+ elevation mediated by Mas-7 occurs through membrane pore formation. 895 10

1-[6-[17 beta-3-Methoxyestra-1,3.5(10)-trien-17-yl]amino]hexyl]-1 H-pyrrole-2,5-dione (U-73122), an inhibitor of processes involved in the activation of phospholipase C, was used to assess the role of phospholipase C activation in the synergistic elevation of cAMP induced by carbachol and prostaglandin E2 in human neuroblastoma (SK-N-BE(2)C cells. Pre-treatment of the cells with U-73122 resulted in inhibition of carbachol-induced intracellular Ca2+ ([Ca2+]i) rise and inositol 1,4,5-trisphosphate (InsP3) generation, with maximal and half maximal inhibition (IC50) occurring at approximately 15 microM and 3.2 microM, respectively. U-731222 also inhibited the synergistic enhancement of cAMP accumulation induced by carbachol and prostaglandin E2 in a concentration-dependent manner with maximum and IC50 at 12 +/- 4 microM and 3.4 +/- 0.3 microM, respectively. However, U-73122 did significantly inhibit prostaglandin E2-induced production. While 1,2-bis(o-aminophenoxy)ethane-N,N,N,'N'-tetraacetic acid (BAPTA/AM) treatment decreased the synergistic cAMP accumulation by 28%m addition U-73122 further decreased it down to complete inhibition. Furthermore, GTP gamma S- and A1F4(-)-induced InsP3 generation in digitonin-mediated permeabilized cells was also inhibited by U-73122 treatment. Pre-treatment of the cells with neomycin, another blocker of the phospholipase C pathway, also resulted in inhibition of the carbachol-induced [Ca2+]i rise, InsP3 generation, and the enhancing effect on cAMP accumulation, to a comparable extent. But, Ca2+ chelation by BAPTA/AM in addition to neomycin treatment further decreased the cAMP accumulation. These results suggest that the increase in cytosolic Ca2+ and the coupling process between muscarinic receptor-like G-protein and phospholipase C are important for the synergistic activation of adenylyl cyclase in SK-N-BE(2)C cells.
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PMID:Synergistic activation of adenylyl cyclase is dependent upon phospholipase C-mediated processes in human neuroblastoma SK-N-BE(2)C cells. 895 41

We report that upon muscarinic stimulation of SK-N-BE(2) human neuroblastoma cells, the extent of phosphoinositide-derived diacylglycerol (DG) conversion to phosphatidic acid (PA), operated by a DG kinase, is dependent on the potency of receptor stimulation and correlates with the reduction of phosphatidylinositol 4,5-bisphosphate mass. Evidence is provided that agonist-evoked Ca2+ mobilisation or protein kinase activation are not key events in triggering receptor-generated DG conversion to PA; furthermore, the phenomenon is compartmentalized, namely it occurs within a topologically restricted area that is poorly accessible to DG artificially generated by cell treatment with bacterial phosphatidylinositol-specific phospholipase C. Possible mechanisms driving regulation of the DG kinase operating in the transduction system investigated are discussed.
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PMID:Phosphoinositide-derived diacylglycerol conversion to phosphatidic acid is a receptor-dependent and compartmentalized phenomenon in human neuroblastoma. 897 96

Thrombin receptor-G protein coupling was investigated in the human epithelial neuroblastoma cell line, SH-EP. In these cells, both alpha-thrombin and thrombin receptor peptides, SFLLRNP (one-letter amino-acid code), which are newly exposed following cleavage by alpha-thrombin, stimulated GTPase activity about 2-fold over basal activity. Pertussis toxin treatment only partially attenuated alpha-thrombin- and SFLLRNP-stimulated GTPase activity by 50%, whereas antibody raised against synthetic heptapeptide SFLLRNP blocked alpha-thrombin-stimulated phosphoinositide hydrolysis more than 80%. Immunoprecipitation studies using this antibody showed that both Gi2, a subtype of guanine nucleotide-binding regulatory proteins (G proteins) mediating inhibition of adenylyl cyclase, and Gq/G11, a G protein mediating stimulation of phospholipase C, were activated by alpha-thrombin. These data suggest that in these cells the thrombin receptor activates pertussis toxin-sensitive and pertussis toxin-insensitive G proteins simultaneously and directly couples to Gi2 and Gq/G11, which mediate different signaling pathways.
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PMID:Direct evidence for two distinct G proteins coupling with thrombin receptors in human neuroblastoma SH-EP cells. 898 57


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