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)

N-terminally shortened analogs of the 27-amino-acid and 38-amino-acid forms of the pituitary-adenylate-cyclase-activating neuropeptide, PACAP(1-27) and PACAP(1-38), were synthesized by a solid-phase method. Systematic deletion of the first 13 amino acids of both PACAP was tested by evaluating their ability to occupy the specific and selective PACAP receptor of human neuroblastoma NB-OK-1 cell membranes and to stimulate adenylate cyclase or, when inactive per se, to inhibit PACAP-stimulated adenylate cyclase activity. For each peptide, the Kact (concentration required for half-maximal adenylate cyclase activation) or Ki [concentration required to shift the dose/response curve of PACAP(1-27) twofold to the right] was in good agreement with the corresponding IC50 [concentration inhibiting 50% of 125I-[AcHis1]PACAP(1-27) binding to membranes], suggesting interaction with the same homogeneous class of adenylate cyclase-coupled receptors. The deletion of the two first amino acids (His1 and Ser2) sufficed to decrease the affinity for receptors and to suppress the capacity to activate adenylate cyclase. The shorter fragments 3-27 and 3-38, 4-27 and 4-38, 5-27 and 5-38, 6-27 and 6-38, 7-27 and 7-38, 8-27 and 8-38, and 9-27 and 9-38 were all competitive antagonists of PACAP(1-27)-stimulated activity with the N-terminally shortened PACAP(1-38) derivatives being 4-30-fold more potent than the equivalent PACAP(1-27) derivatives. In this group PACAP(6-38) was the most potent antagonist (Ki 1.5 nM). Surprisingly, the N-terminally shorter fragments 10-27 and 10-38, 11-27 and 11-38, 12-27 and 12-38, 13-27 and 13-38, and 14-27 and 14-38 were again able to stimulate adenylate cyclase, the smallest fragments, PACAP(14-27) and PACAP(14-38), being the most potent and efficient (Kact 2 microM and 0.1 microM, respectively). In this group of agonists, PACAP(1-38) derivatives deleted at the N-terminus were also more potent than the equivalent PACAP(1-27) derivatives.
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PMID:Antagonistic properties are shifted back to agonistic properties by further N-terminal shortening of pituitary adenylate-cyclase-activating peptides in human neuroblastoma NB-OK-1 cell membranes. 132 69

Compound BM5 [N-methyl-N(1-methyl-4-pyrrolidino-2-butynyl) acetamide] has previously been described as an agonist at postsynaptic muscarinic receptors and as an antagonist at presynaptic receptors. In the current work, we studied the ability of this compound to selectively stimulate phosphoinositide (PI) turnover in Chinese hamster ovary cells transfected with m1 muscarinic receptors and in SK-N-SH neuroblastoma cells that express only m3 receptors. We also studied the ability of this compound to stimulate adenylate cyclase inhibition in m2 muscarinic receptors from heart tissue and in m4 receptors expressed in NG108-15 cells. BM5 stimulated the two muscarinic receptor subtypes coupled to adenylate cyclase inhibition. In NG108-15 cells, 100 microM BM5 inhibited prostaglandin E1-stimulated cAMP formation by 36 +/- 1.5%, whereas 100 microM of the full agonist oxotremorine-M inhibited cAMP formation by 64.1 +/- 1.9%. The half-maximal concentration for BM5 inhibition of cAMP formation was 0.4 +/- 0.1 microM. In heart membranes, BM5 inhibited isoproterenol-stimulated adenylate cyclase by 24 +/- 2%, whereas oxotremorine inhibited this activity by 34 +/- 3%. In contrast to its activity at these receptor subtypes, BM5 did not stimulate the m1 or m3 receptor subtypes, which couple to PI turnover. In these latter two subtypes, BM5 inhibited oxotremorine-M-stimulated PI turnover with IC50 values of 10-20 microM. Therefore, BM5 is a partial agonist at adenylate cyclase-coupled muscarinic receptor subtypes and is a pure antagonist at PI turnover-coupled muscarinic receptor subtypes. These studies also suggest that, at least in some parts of the brain, postsynaptic muscarinic receptors are coupled to adenylate cyclase, whereas presynaptic muscarinic receptors are coupled to PI turnover.
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PMID:An agonist that is selective for adenylate cyclase-coupled muscarinic receptors. 255 Jul 80

Cultured NCB-20 mouse neuroblastoma X Chinese hamster brain clonal hybrid cells express an adenylate cyclase-coupled receptor for serotonin (5HT) which corresponds pharmacologically to the 5HT1 receptor in whole brain, except for its much lower affinity for serotonin. Studies showed that the affinity of the NCB-20 receptor could be increased to near that of the whole brain receptor and the potency of 5HT in elevating cyclic AMP levels increased by pre-incubating NCB-20 cells for at least 3 hours with submicromolar concentrations of brain gangliosides. Tetrasialoganglioside (GQ1b) was found to be the most potent ganglioside tested, producing a ten-fold increase in affinity. However, the actual 5HT binding site is a protein and we have obtained no evidence that serotonin binds directly to gangliosides at the concentrations at which it labels the receptor. The receptor-mediated inhibition of adenylate cyclase by biogenic amines such as dopamine and clonidine through dopamine (D2) and alpha-adrenoreceptors was unaffected by pre-incubation of the NCB-20 cells with gangliosides. Enkephalin was also found to acutely supress both the ability of 5HT to stimulate adenylate cyclase activity and the synthesis of polysialogangliosides in NCB-20 cells. After 6 hours of exposure, the cells became tolerant to enkephalin and after 36 hours the cells became supersensitive to 5HT in terms of adenylate cyclase activation and 5HT binding. The affinity of the receptor for 5HT increased the same 10-fold magnitude as achieved by GQ1b pre-incubation in comparison with untreated cells. This increase in receptor affinity appeared to coincide chronologically with the increase in ganglioside synthesis observed in enkephalin tolerant cells, further suggesting an important role of polysialogangliosides in the function of the serotonin (5HT1) receptor.
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PMID:Gangliosides as modulators of the coupling of neurotransmitters to adenylate cyclase. 614 53

The present article investigates chronic opioid regulation of the stimulatory adenylate cyclase-coupled prostaglandin E1 (PGE1) receptor system in neuroblastoma x glioma (NG108-15) hybrid cells. Persistent activation of delta-opioid receptors by morphine (10 mumol/L; 3 days) substantially down-regulates the number of PGE1 binding sites by approximately 30%, without affecting their affinity. Radioligand binding studies performed in the presence of GTP gamma S (100 mumol/L) further revealed that the remaining PGE1 binding sites are still capable of interacting functionally with their associated stimulatory G proteins, Gs. On the postreceptor level, neither changes in the abundance nor in the intrinsic activity of the alpha subunit of Gs (Gs alpha) were found during the state of opioid dependence, as has been verified by western blot and S49 cyc- reconstitution experiments, respectively. Evaluation of the functional interaction between PGE1 receptors and Gs by means of receptor-stimulated, cholera toxin-catalyzed ADP-ribosylation of Gs alpha revealed a significant increase in the ability of PGE1 receptors to activate Gs alpha (3.3-fold increase in EC50; p < 0.05) in cells chronically exposed to morphine. This effect was completely blocked by coincubation of the cells together with the opiate antagonist naloxone (100 mumol/L; 3 days), whereas precipitation of morphine withdrawal by naloxone (100 mumol/L) had no further effect on sensitization in PGE1 receptor/Gs coupling. These findings provide evidence that the stimulatory adenylate cyclase-coupled PGE1 receptor system represents a potential target of chronic delta-opioid receptor activation in NG108-15 hybrid cells. They further suggest that sensitization in stimulatory signal transduction plays a critical role in the generation of opioid dependence.
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PMID:Chronic activation of inhibitory delta-opioid receptors cross-regulates the stimulatory adenylate cyclase-coupled prostaglandin E1 receptor system in neuroblastoma x glioma (NG108-15) hybrid cells. 776 24

Prolonged exposure of neuroblastoma x glioma (NG 108-15) hybrid cells to inhibitory acting drugs results in sensitization of adenylate cyclase. We now report that chronic activation (3 days) of either inhibitory delta-opioid receptors, alpha 2B-adrenoceptors, or muscarinic M4 receptors significantly decreases the number of stimulatory, adenylate cyclase-coupled prostaglandin E1 receptors. Pharmacological characterization further revealed that the loss of [3H]prostaglandin E1-binding sites most likely corresponds to a reduction of the number of high-affinity, G protein-coupled prostaglandin E1 receptors. The decline in functionally active prostaglandin E1 receptors developed in a time- and dose-dependent manner and could be prevented by pretreatment of the cells with pertussis toxin. Heterologous prostaglandin E1 receptor regulation was blocked by concomitant exposure of the cells to antagonists for inhibitory receptors and was rapidly reversed (t 1/2 < 30 min) upon termination of chronic inhibitory drug treatment. The decrease in high-affinity prostaglandin E1 receptors developed regardless of whether full or partial agonists were used for pretreatment. In addition, the concentrations of inhibitory drugs required to maximally affect prostaglandin E1 receptor number closely resembled those mediating maximal adenylate cyclase inhibition. The data demonstrate that chronic inhibitory drug treatment of NG 108-15 hybrid cells reduces the number of functionally active, excitatory prostaglandin E1 receptors. Thus, it is proposed that adaptations at the level of stimulatory receptor systems contribute to the regulatory mechanisms associated with drug dependence.
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PMID:Chronic exposure of NG 108-15 cells to inhibitory acting drugs reduces stimulatory prostaglandin E1 receptor number. 879 Oct 8

Chronic exposure of all-trans-retinoic acid-differentiated SH-SY5Y cells to morphine (10 mu M; 2 days) results in sensitization of adenylate cyclase as characterized by a significant increase in both PGE1 receptor-mediated as well as receptor-independent (NaF, 10 mM; forskolin, 100 mu M) stimulation of effector activity. To investigate the underlying biochemical alterations, chronic opioid regulation of each of the components comprising the stimulatory PGE1 receptor system was examined. On receptor level, chronic morphine treatment was found to reduce PGE1 receptor number (Bmax) by approximately 40%, whereas their affinity slightly increased. Binding experiments performed in the presence of GTPgammaS (100 mu M) further indicate that the decrease in PGE1 receptor density is associated with a loss of functionally G protein-coupled receptors. On post-receptor level, chronic morphine treatment substantially increased the abundance and functional activity of stimulatory G proteins, as assessed by cholera toxin-catalyzed ADP-ribosylation of GSalpha and S49 cyc- reconstitution assays. No changes were found on the level of adenylate cyclase. Evaluation of the functional interaction between PGE1 receptors and GS in situ by application of a C-terminal anti-GSalpha antibody revealed a more intense coupling efficiency between these two entities, since a significant higher amount of antibody (2.3-fold) was required in morphine dependent cell membranes to half-maximally attenuate PGE1 receptor-stimulated adenylate cyclase activity. In addition, limitation of the amount of functionally available GSalpha within the PGE1 receptor/adenylate cyclase signal transduction cascade abolished the generation of a supersensitive adenylate cyclase response during the state of naloxone (100 mu M)-precipitated withdrawal. These data demonstrate that in human neuroblastoma SH-SY5Y cells chronic morphine-induced sensitization of adenylate cyclase is associated with distinct quantitative and qualitative adaptations within the stimulatory adenylate cyclase-coupled PGE1 receptor system. Thus, alterations in the functional activity of stimulatory receptor systems are suggested to contribute to the cellular mechanisms underlying opioid dependence.
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PMID:Morphine dependence in human neuroblastoma SH-SY5Y cells is associated with adaptive changes in both the quantity and functional interaction of PGE1 receptors and stimulatory G proteins. 891 1