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)

Activation of the delta-opioid receptor in NG108-15 neuroblastoma X glioma hybrid cells results in a transient increase at the intracellular level of inositol-1,4,5-triphosphate [Ins(1,4,5)P3]. This time course in the transient increase in the Ins(1,4,5)P3 level is distinctly different from that observed in the homologous opioid receptor desensitization as measured by the inhibition of adenylyl cyclase activity. One probable mechanism for this rapid loss in Ins(1,4,5)P3 response is the feedback regulation of the phospholipase C activity. Regulation by protein phosphorylation was suggested by the observations that the opioid-mediated response was potentiated by calphostin C, an inhibitor of protein kinase C (PKC), and was abolished by either phorbol-12-myristate-13-acetate, a PKC activator, or calyculin A, a protein phosphatase1/2A inhibitor. The direct phosphorylation of phospholipase C was demonstrated by immunoprecipitation of PLC-beta3 from metabolically labeled NG108-15 cells challenged with the delta-selective agonist [D-Pen2, D-Pen5]enkephalin (DPDPE). A time- and DPDPE concentration-dependent and naloxone-reversible increase in the PLC-beta3 phosphorylation can be demonstrated. This PLC-beta3 phosphorylation was mainly due to PKC activation because pretreatment of NG108-15 cells with calphostin C could block the DPDPE effect. Activation of the PLC-beta3 by DPDPE was one of the prerequisites for agonist-mediated PLC-beta3 phosphorylation because the aminosteroid phospholipase C inhibitor U73122 could block the DPDPE effect. In addition to DPDPE, lysophosphatidic acid (LPA) stimulated the PLC-beta3 phosphorylation, but bradykinin did not. Furthermore, the LPA- and DPDPE-mediated PLC-beta3 phosphorylation was additive and was much less than that observed with phorbol-12-myristate-13-acetate. The effect of DPDPE was specific to PLC-beta3; the betagamma-insensitive phospholipase C-beta1 was not phosphorylated in the presence of either DPDPE or LPA. These results indicate that although PKC phosphorylation of PLC-beta3 is not obligatory for the opioid receptor desensitization, it seems to play a significant facilatory role in the mechanisms allowing desensitization of opioid-activated phospholipase C response before that of adenylyl cyclase inhibition.
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PMID:Contribution of phospholipase C-beta3 phosphorylation to the rapid attenuation of opioid-activated phosphoinositide response. 961 7

1. We have used previously characterized clones of the human neuroblastoma cell line, SH-SY5Y. constitutively expressing either the human 5-HT2A or 5-HT2C receptor to compare their desensitization profiles after exposure to 5-HT. 2. 5-HT stimulated [3H]-inositol phosphate ([3H]-IPx) production at both the 5-HT2C (pEC50=8.03+/-0.15) and 5-HT2A receptors (pEC50=7.15+/-0.08), with maximal responses occurring after exposure to 1 microM and 10 microM 5-HT, respectively. 3. Exposure of cells to maximally effective concentrations of 5-HT caused time- and concentration-dependent desensitization of [3H]-IPx formation. The 5-HT2A response desensitized slower (t1/2 = 110 min) and with lower sensitivity than that of the 5-HT2C receptor (t1/2 = 12.5 min). In each case, desensitization was blocked by co-administration of a specific receptor antagonist. Following exposure to 10 microM 5-HT for 2 h, both receptors exhibited extensive desensitization, with subsequent responses to 5-HT reduced by more than 80%. 4. 5-HT stimulated Ins(1,4,5)P3 production with a potency similar to that for [3H]-IPx production at each receptor. In both cases Ins(1,4,5)P3 levels peaked rapidly then returned to basal level within a short time. This peak consistently occurred earlier for the 5-HT2C receptor (5 s) than for the 5-HT2A receptor (20 s). 5. Prior exposure of SH-SY5Y/5-HT2C cells to 5-HT (1 microM/15 min) caused a significant decrease in the 5-HT-stimulated peak in Ins(1,4,5)P3 levels whereas no such change occurred in SH-SY5Y/5-HT2A cells following exposure to 10 microM 5-HT for 15 min. 6 These results indicate that the human 5-HT2A and 5-HT2C receptors both exhibit desensitization at the level of inositol phosphate formation when expressed in the same cellular environment, with the 5-HT2C receptor being more sensitive to 5-HT-mediated desensitization than the 5-HT2A receptor.
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PMID:Comparative desensitization of the human 5-HT2A and 5-HT2C receptors expressed in the human neuroblastoma cell line SH-SY5Y. 983 8

Agonist stimulation causes the endocytosis of many G protein-coupled receptors, including muscarinic acetylcholine receptors. In this study we have investigated the agonist-triggered trafficking of the M3 muscarinic receptor expressed in SH-SY5Y human neuroblastoma cells. We have compared the ability of a series of agonists to generate the second messenger Ins(1,4,5)P3 with their ability to stimulate receptor endocytosis. We show that there is a good correlation between the intrinsic activity of the agonists and their ability to increase the rate constant for receptor endocytosis. Furthermore, on the basis of our results, we predict that even very weak partial agonists should under some circumstances be able to cause substantial receptor internalization. Receptor endocytosis occurs too slowly to account for the rapid desensitization of the Ca2+ response to carbachol. Instead, receptor endocytosis and recycling appear to play an important role in resensitization. After an initial agonist challenge, the response to carbachol is fully recovered when only about half of the receptors have been recycled to the cell surface, suggesting that there is a receptor reserve of about 50%. Removal of this reserve by receptor alkylation significantly reduces the extent of resensitization. Resensitization is also reduced by inhibitors of either endocytosis alone (concanavalin A) or of endocytosis and recycling (nigericin). Finally, the protein phosphatase inhibitor calyculin A also reduces resensitization, possibly by blocking the dephosphorylation of the receptors in an endosomal compartment.
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PMID:Endocytosis and recycling of muscarinic receptors. 1006 14

1. Differentiation of SH-SY5Y neuroblastoma cells induces morphological and biochemical changes consistent with a more neuronal phenotype. These cells may therefore provide a model for studying phenomena such as signal transduction in a neuronal context whilst retaining the advantages of a homogenous cell population expressing a well characterized array of G-protein coupled receptors. 2. This study examined the effects of differentiating SH-SY5Y cells on muscarinic- and bradykinin-receptor-mediated phosphoinositide and Ca2+ signalling. Retinoic acid (10 microM, 6 days) along with a lowered serum concentration produced phenotypic changes consistent with differentiation including reduced proliferation and increased neurite outgrowth. 3. Differentiation increased the magnitude and potency of rapid Ins(1,4,5)P3 responses to a full muscarinic receptor agonist. Bradykinin receptor-mediated Ins(1,4,5)P3 signalling was also potentiated following differentiation. Determination of agonist-evoked accumulation of [3H]-inositol phosphates under lithium-block demonstrated these changes reflected enhanced phospholipase C activity which is consistent with observed increases in the expression of muscarinic and bradykinin receptors. 4. Despite the marked alterations in Ins(1,4,5)P3 signalling following differentiation, elevations of intracellular [Ca2+] were totally unaltered. Thus, in SH-SY5Y cells, the relationship between the elevations of Ins(1,4,5)P3 and intracellular [Ca2+] is agonist dependent and affected by the state of differentiation. This demonstrates that mechanisms other than the measured increase in Ins(1,4,5)P3 regulate the elevation of intracellular [Ca2+].
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PMID:Complex relationship between Ins(1,4,5)P3 accumulation and Ca2+ -signalling in a human neuroblastoma reveled by cellular differentiation. 1032 87

In adherent SH-SY5Y human neuroblastoma cells, activation of G-protein-coupled muscarinic M3 receptors evoked a biphasic elevation of both intracellular [Ca(2+)] ([Ca(2+)]i) and inositol-1,4,5-trisphosphate (D-Ins(1,4,5)P3) mass. In both cases, temporal profiles consisted of rapid transient elevations followed by a decline to a lower, yet sustained level. In contrast, platelet-derived growth factor (PDGF), a receptor tyrosine kinase agonist acting via PDGF receptor b chains in these cells, elicited a slow and transient elevation of [Ca(2+)]i that returned to basal levels within 5 to 10 min with no evidence of inositol phosphate generation. Full responses for either receptor type required intracellular and extracellular Ca(2+) and mobilization of a shared thapsigargin-sensitive intracellular Ca(2+) store. Strategies that affected the ability of D-Ins(1,4,5)P3 to interact with the Ins(1,4,5)P3-receptor demonstrated an Ins(1,4,5)P3-dependency of the muscarinic receptor-mediated elevation of [Ca(2+)]i but showed that PDGF-mediated elevations of [Ca(2+)]i are Ins(1,4,5)P3-independent in these cells.
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PMID:Inositol 1,4,5-trisphosphate-independent calcium signalling by platelet-derived growth factor in the human SH-SY5Y neuroblastoma cell. 1144 Apr 67

Testosterone has short- and long-term roles in regulating neuronal function. Here, we show rapid intracellular androgen receptor-independent effects of testosterone on intracellular Ca2+ in neuroblastoma cells. We identified testosterone-induced Ca2+ signals that began primarily at the neurite tip, followed by propagation towards the nucleus, which was then repeated to create an oscillatory pattern. The initial transient depended upon production of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], but subsequent transients required both extracellular Ca2+ influx and Ca2+ release from intracellular stores. Inhibition of pertussis toxin-sensitive G-protein receptors or the use of siRNA for the Ins(1,4,5)P3 receptor type 1 blocked the Ca2+ response, whereas inhibition or knock-down of the intracellular androgen receptor was without effect. Cytosolic and nuclear Ca2+ were buffered with parvalbumin engineered to be targeted to the cytosol or nucleus. Cytoplasmic parvalbumin blocked Ca2+ signaling in both compartments; nuclear parvalbumin blocked only nuclear signals. Expression of a mutant parvalbumin did not modify the testosterone-induced Ca2+ signal. Neurite outgrowth in neuroblastoma cells was enhanced by the addition of testosterone. This effect was inhibited when cytosolic Ca2+ was buffered and was attenuated when parvalbumin was targeted to the nucleus. Our results are consistent with a fast effect of testosterone, involving Ins(1,4,5)P3-mediated Ca2+ oscillations and support the notion that there is synergism in the pathways used for neuronal cell differentiation involving rapid non-genomic effects and the classical genomic actions of androgens.
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PMID:Ca2+ oscillations induced by testosterone enhance neurite outgrowth. 1644 26


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