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)

The opioid receptor-like (ORL1) receptor regulates a variety of effectors shared by its close relatives, the opioid receptors. Supersensitization of adenylyl cyclase (AC) is a hallmark of cellular tolerance induced by chronic activation of opioid receptors. To examine if chronic activation of the ORL1 receptor leads to a similar adaptation, a HEK293 cell line stably expressing the human ORL1 receptor (293/ORL1) was established. Chronic treatment of 293/ORL1 cells with nociceptin/OFQ resulted in enhanced AC activity in response to forskolin stimulation. The AC supersensitivity was blocked by pertussis toxin, indicating the involvement of Gi/Go proteins. Likewise, chronic activation of endogenous ORL1 receptors in the neuroblastoma SK-N-SH cells led to Gi/Go-mediated AC supersensitization.
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PMID:Chronic activation of ORL1 receptor induces supersensitization of adenylyl cyclase. 1054 94

1 The D3 dopamine receptor presumably activates Gi/Go subtypes of G-proteins, like the structurally analogous D2 receptor, but its signalling targets have not been clearly established due to weak functional signals from cloned receptors as heterologously expressed in mostly non-neuronal cell lines. 2 In this study, recombinant human D3 receptors expressed in a human neuroblastoma cell line, SH-SY5Y, produced much greater signals than those expressed in a human embryonic kidney cell line, HEK293. Quinpirole, a prototypic agonist, markedly inhibited forskolin-stimulated cyclic AMP production and Ca2+-channel (N-type) currents in SH-SY5Y cells, and enhanced GTPgamma35S binding in isolated membranes, nearly ten times greater than that observed in HEK293 cell membranes. 3 GTPgamma35S-bound Galpha subunits from quinpirole-activated and solubilized membranes were monitored upon immobilization with various Galpha-specific antibodies. Galphao subunits (not Galphai) were highly labelled with GTPgamma35S in SH-SY5Y, but not in HEK293 cell membranes, despite their abundance in the both cell types, as shown with reverse transcription-polymerase chain reaction and Western blots. N-type Ca2+ channels and adenylyl cyclase V (D3-specific effector), on the other hand, exist only in SH-SY5Y cells. 4 More efficient coupling of the D3 receptor to Go subtypes in SH-SY5Y than HEK293 cells may be attributed, at least in part, to the two D3 neuronal effectors only present in SH-SY5Y cells (N-type Ca2+-channels and adenylyl cyclase V). The abundance of Go subtypes in the both cell lines seems to indicate their availability not a limiting factor.
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PMID:Efficient functional coupling of the human D3 dopamine receptor to G(o) subtype of G proteins in SH-SY5Y cells. 1057 30

Receptors for pituitary adenylyl cyclase activating peptide (PACAP) have been identified in human SH-SY5Y neuroblastoma cells with PACAP being 1000-fold more potent than vasoactive intestinal peptide (VIP) in [(125)I]PACAP binding inhibition and stimulation of cAMP accumulation. Maxadilan, a vasodilator peptide from the salivary gland of the sand fly Lutzomyia longipalpis also specifically bound to SH-SY5Y cells, and was equipotent to PACAP in [(125)I]PACAP and [(125)I]maxadilan binding inhibition, and stimulation of cAMP accumulation. Maxadilan and PACAP also increased the cytosolic free calcium concentration. In human SK-N-MC neuroblastoma cells PACAP, VIP and maxadilan equipotently stimulated cAMP accumulation. The maximal effects of VIP and maxadilan were additive and reached those of PACAP alone. In human T47D breast carcinoma cells PACAP and VIP were also equipotent in the stimulation of cAMP accumulation, but maxadilan was inactive. The results are consistent with the interaction of maxadilan with PACAP specific PAC(1)receptors in SH-SY5Y cells, but not with VPAC receptors, not differentiating between VIP and PACAP in T47D cells. Moreover, maxadilan is a PAC(1)receptor specific agonist which allows discrimination of co-expressed PAC(1)and VPAC receptors in SK-N-MC cells.
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PMID:Maxadilan interacts with receptors for pituitary adenylyl cyclase activating peptide in human SH-SY5Y and SK-N-MC neuroblastoma cells. 1065 79

Human neuroblastoma SH-SY5Y cells express endogenous mu-opioid receptor and develop cellular tolerance to morphine after prolonged (>/=4 h) treatment with morphine. Treatment with forskolin (25 microM, 12 h), an adenylyl cyclase activator, also desensitized mu-opioid receptor response to morphine (10 microM) by 38% (P<0. 001), which was reversed by the cyclic AMP (cAMP) dependent kinase inhibitor N-(2-aminoethyl)-5-isoquinolinesulfonamide (H8) (100 microM). Treatment with both morphine and forskolin appeared to cause an additive effect in desensitizing mu-opioid receptor. In mu-opioid receptor stably transfected human embryonic kidney 293 (HEK-mu) cells, morphine treatment produced cAMP upregulation, yet failed to induce mu-opioid receptor tolerance. However, treatment with forskolin (25 microM) or 8-bromo-cAMP (1mM) led to profound mu-opioid receptor tolerance, which was reversed by H8. These results demonstrate that cAMP-dependent kinase activation causes mu-opioid receptor tolerance. However, morphine-induced mu-opioid receptor tolerance in SH-SY5Y cells is not mediated by cAMP-dependent kinase activation. In addition, our results indicate that cAMP-upregulation does not necessarily lead to mu-opioid receptor tolerance.
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PMID:Tolerance to morphine at the mu-opioid receptor differentially induced by cAMP-dependent protein kinase activation and morphine. 1068 80

The microtubule protein tubulin regulates adenylyl cyclase and phospholipase Cbeta(1) (PLCbeta(1)) signaling via transactivation of the G-protein subunits Galphas, Galphai1, and Galphaq. Because most tubulin is not membrane associated, this study investigates whether tubulin translocates to the membrane in response to an agonist so that it might regulate G-protein signaling. This was studied in SK-N-SH neuroblastoma cells, which possess a muscarinic receptor-regulated PLCbeta(1)-signaling pathway. Tubulin, at nanomolar concentrations, transactivated Galphaq by the direct transfer of a GTP analog and potentiated carbachol-activated PLCbeta(1). A specific and time-dependent association of tubulin with plasma membranes was observed when SK-N-SH cells were treated with carbachol. The same phenomenon was observed with membranes from Sf9 cells, expressing a recombinant PLCbeta(1) cascade. The time course of this event was concordant both with transactivation of Galphaq by the direct transfer of [(32)P]P(3)(4-azidoanilido)-P(1)-5'-GTP from tubulin as well as with the activation of PLCbeta(1). In SK-N-SH cells, carbachol induced a rapid and transient translocation of tubulin to the plasma membrane, microtubule reorganization, and a change in cell shape as demonstrated by confocal immunofluorescence microscopy. These observations presented a spatial and temporal resolution of the sequence of events underlying receptor-evoked involvement of tubulin in G-protein-mediated signaling. It is suggested that G-protein-coupled receptors might modulate cytoskeletal dynamics, intracellular traffic, and cellular architecture.
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PMID:Muscarinic receptor activation promotes the membrane association of tubulin for the regulation of Gq-mediated phospholipase Cbeta(1) signaling. 1075 28

We have previously shown that N18TG2 neuroblastoma cells express the type 6 adenylyl cyclase and that preincubation with nitric oxide (NO) attenuates Gs- and forskolin-stimulated activity. Here we show that this inhibition reflects a direct action of NO on the adenylyl cyclase. Preincubation of N18TG2 cell membranes and insect cell membranes expressing recombinant type 5 and type 6 isoforms with NO donors leads to an inhibition of forskolin-stimulated adenylyl cyclase activity. NO donors do not alter the type 1 (representative of the type 1,3,8 family) or type 2 (representative of the type 2,4, 7 family) isoforms expressed in insect cells, even under conditions of compromised assay conditions or a range of temperatures. Thus, the ability of NO to inhibit adenylyl cyclase stimulation is dependent upon the nature of the isoform present, and appears to represent a unique regulation of the type 5,6 isoform family.
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PMID:Nitric oxide selectively inhibits adenylyl cyclase isoforms 5 and 6. 1078 30

Previously, we reported that the time course for the rapid phosphorylation rate of mu-opioid receptor expressed in human embryonic kidney (HEK)293 cells did not correlate with the slow receptor desensitization rate induced by [D-Ala(2),N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO). However, others have suggested that receptor phosphorylation is the trigger for mu-opioid receptor desensitization. In this study, we demonstrated the relatively slow rate of receptor desensitization could be attributed partially to the recycling of internalized receptor as determined by fluorescence-activated cell-sorting analysis. However, the blockade of the endocytic and Golgi transport events in HEK293 cells with monensin and brefeldin A did not increase the initial rate of receptor desensitization. But the desensitization rate was increased by reduction of the mu-opioid receptor level with beta-furnaltrexamine (betaFNA). The reduction of the receptor level with 1 microM betaFNA significantly increased the rate of etorphine-induced receptor desensitization. By blocking the ability of receptor to internalize with 0.4 M sucrose, a significant degree of receptor being rapidly desensitized was observed in HEK293 cells pretreated with betaFNA. Hence, mu-opioid receptor is being resensitized during chronic agonist treatment. The significance of resensitization of the internalized receptor in affecting receptor desensitization was demonstrated further with human neuroblastoma SHSY5Y cells that expressed a low level of mu-opioid receptor. Although DAMGO could not induce a rapid desensitization in these cells, in the presence of monensin and brefeldin A, DAMGO desensitized the mu-opioid receptor's ability to regulate adenylyl cyclase with a t(1/2) = 9.9 +/- 2.1 min and a maximal desensitized level at 70 +/- 4.7%. Furthermore, blockade of receptor internalization with 0.4 M sucrose enhanced the DAMGO-induced receptor desensitization, and the inclusion of monensin prevented the resensitization of the mu-opioid receptor after chronic agonist treatment in SHSY5Y cells. Thus, the ability of the mu-opioid receptor to resensitize and to recycle, and the relative efficiency of the receptor to regulate adenylyl cyclase activity, contributed to the observed slow rate of mu-opioid receptor desensitization in HEK293 cells.
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PMID:Receptor density and recycling affect the rate of agonist-induced desensitization of mu-opioid receptor. 1090 7

Rat synaptotagmin IV (SYT IV) is a depolarization-inducible synaptic vesicle protein. SYT IV homozygous mutant mice are viable and have deficits in fine motor coordination and some forms of memory. In this study, we report the identification of a human SYT IV orthologue. The predicted amino acid sequence of the human SYT IV clone is nearly 90% identical to the rat and mouse SYT IV proteins. In addition, human SYT IV has a characteristic serine for aspartate substitution within the first C2 domain that is conserved among Drosophila, Caenorhabditis elegans, mouse, and rat SYT IV sequences. The human SYT IV gene maps to chromosome band 18q12.3, a region that defines a break point in the synteny with mouse chromosome 18 and has been implicated by associated markers in two human psychiatric disorders. In the human neuroblastoma cell line SK-N-SH, SYT IV is an immediate-early gene inducible by elevated intracellular calcium and by forskolin, an activator of adenylyl cyclase. Expression of human SYT IV mRNA is restricted to brain and is not detectable in non-neuronal tissues. Within brain, human SYT IV mRNA is most highly expressed in hippocampus, with lower levels present in amygdala and thalamus. These results suggest a role for SYT IV in human brain function and in human neurological disease.
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PMID:The human synaptotagmin IV gene defines an evolutionary break point between syntenic mouse and human chromosome regions but retains ligand inducibility and tissue specificity. 1093 84

Two subtypes of cannabinoid receptors are currently recognized, CB(1), found in brain and neuronal cells, and CB(2), found in spleen and immune cells. We have characterized 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxyl ic acid phenylamide (CP-272871) as a novel aryl pyrazole antagonist for the CB(1) receptor. CP-272871 competed for binding of the cannabinoid agonist (3)H-labeled (-)-3-[2-hydroxy-4-(1, 1-dimethylheptyl)-phenyl]-4-[3-hydroxypropyl]cyclohexan-1-ol ([(3)H]CP-55940) at the CB(1) receptor in rat brain membranes with a K(d) value 20-fold greater than that of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A). CP-272871 also competed for binding with the aminoalkylindole agonist (3)H-labeled (R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]1, 4-benzoxazin-6-yl](1-naphthyl)methanone ([(3)H]WIN-55212-2), as well as the aryl pyrazole antagonist [(3)H]SR141716A. Inverse agonist as well as antagonist properties were observed for both SR141716A and CP-272871 in signal transduction assays in biological preparations in which the CB(1) receptor is endogenously expressed. SR141716A augmented secretin-stimulated cyclic AMP (cAMP) accumulation in intact N18TG2 neuroblastoma cells, and this response was reversed by the agonist desacetyllevonantradol. CP-272871 antagonized desacetyllevonantradol-mediated inhibition of adenylyl cyclase in N18TG2 membranes, and increased adenylyl cyclase activity in the absence of agonist. SR141716A and CP-272871 antagonized desacetyllevonantradol-stimulated (35)S-labeled guanosine-5'-O-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) binding to brain membrane G-proteins, and decreased basal [(35)S]GTPgammaS binding to G-proteins. K(+) enhanced CP-272871 and SR141716A inverse agonist activity compared with Na(+) or NMDG(+) in the assay. These results demonstrated that the aryl pyrazoles SR141716A and CP-272871 behave as antagonists and as inverse agonists in G-protein-mediated signal transduction in preparations of endogenously expressed CB(1) receptors.
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PMID:Inverse agonist properties of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A) and 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxyl ic acid phenylamide (CP-272871) for the CB(1) cannabinoid receptor. 1100 25

Chronic opioid regulation of stimulatory receptor activity was investigated in neuroblastoma x glioma (NG108-15) hybrid cells stably transfected to express the human beta(2)-adrenoceptor (beta(2)-AR). Expressed beta(2)-ARs are functionally coupled to G proteins and display ligand-independent signalling activity, as demonstrated by the ability of an inverse agonist to attenuate basal adenylyl cyclase (AC) activity. Despite the relative increase in basal AC activity due to the development of tolerance/dependence, chronic morphine treatment was found to completely abolish spontaneous beta(2)-AR activity by reducing basal receptor/G protein precoupling. A similar chronic opioid effect was observed in transiently transfected COS-7 cells. These results indicate that during the state of opioid tolerance/dependence basal levels of AC activity are no longer under the control of spontaneously active stimulatory receptors.
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PMID:Opioid tolerance/dependence in neuroblastoma x glioma (NG108-15) hybrid cells is associated with a reduction in spontaneous stimulatory receptor activity. 1109 59


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