Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of activation of the adenylyl cyclase-protein kinase A pathway on the expression of delta-opioid receptor mRNA in the NG108-15 neuroblastoma x glioma cell line has been investigated. Activation of prostaglandin E1 (PGE1) receptors, which are positively coupled to adenylyl cyclase, resulted in a reduction in delta-receptor messenger RNA levels. Direct stimulation of adenylyl cyclase by forskolin or treatment of cells with the cyclic AMP analogue dibutyryl cyclic AMP (db-cAMP) mimicked the effect of PGE1. Down-regulation in receptor protein levels, as measured by loss of radioligand binding sites, was also observed and its extent correlated well with the decrease in the amount of delta-opioid receptor transcripts. D-Ser2-Leu-enkephalin-Thr6 (DSLET) inhibition of adenylyl cyclase activity was also diminished after db-cAMP treatment. Inhibitors of protein kinase A (PKA) partially reversed the PGE1- and db-cAMP-mediated repression of the delta-opioid receptor mRNA levels. The rate of degradation of delta-opioid receptor mRNA in the presence of actinomycin D was not altered in response to db-cAMP, suggesting that mRNA stability is not reduced by PKA action. The regulation of delta-opioid receptor mRNA levels by db-cAMP was not sensitive to the protein synthesis inhibitor cycloheximide, suggesting that de novo protein synthesis is not required in this process.
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PMID:Regulation of delta-opioid receptor mRNA levels by receptor-mediated and direct activation of the adenylyl cyclase-protein kinase A pathway. 900 47

Coadministration of antagonists of N-methyl-D-aspartate (NMDA) receptor and opioids has been shown to prevent development of opiate tolerance in animal and clinical studies, but its cellular and molecular mechanisms are not understood. In this study, the effect of NMDA on delta-opioid receptor (DOR)-mediated signal transduction was investigated in neuroblastoma x glioma NG108-15 cells that functionally express both DOR and NMDA receptors. Acute incubation of NG108-15 cells with NMDA, a specific agonist of NMDA receptor, significantly attenuated the ability of DOR agonist [D-Pen2, D-Pen5]-enkephalin (DPDPE) to inhibit forskolin-stimulated cAMP production. The attenuation caused by NMDA was dose-dependent, and the EC50 of DPDPE increased 100-fold (from 4.6 nM to 500 nM) after NMDA treatment. The NMDA effect on responsiveness of delta-opioid receptors to DPDPE could be blocked by ketamine, a NMDA receptor-specific antagonist. This NMDA attenuation effect on DOR activity was also observed in neuronal primary cell cultures from fetal mouse brain but not in the Chinese hamster ovary cell line stably transfected with DOR alone. Interestingly, NMDA pretreatment reduced the cellular response to epinephrine but not to that of prostaglandin E1 in NG108-15 cells, which suggests differential modulation of NMDA on different G protein-coupled receptors. Pretreatment of NG108-15 cells with ketamine along with DPDPE greatly attenuated DPDPE-induced acute desensitization of DOR. Furthermore, the specific inhibitors of protein kinase C, either chelerythrine chloride or Go 6979, effectively blocked the NMDA effect, which indicates the involvement of protein kinase C in the process. In conclusion, the activation of NMDA receptors can attenuate acute responsiveness of DOR in neuronal cells, whereas its blockage leads to reduction of DOR desensitization. These results have thus provided an insight into cross-talk between NMDA and opioid signal transduction.
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PMID:Activation of N-methyl-D-aspartate receptor attenuates acute responsiveness of delta-opioid receptors. 910 22

Chronic exposure of neuroblastoma x glioma (NG108-15) cells to substances that elevate intracellular cAMP levels results in morphological differentiation into a more neuronal-like phenotype. Here we report that forskolin-induced differentiation is accompanied by a biphasic regulation of stimulatory adenylyl cyclase (AC) signaling. While 1 day of forskolin exposure produces an initial increase in basal, [AIF4](-)-, and prostaglandin E1 (PGE1)-stimulated AC activities, stimulatory signal transduction is substantially reduced after complete differentiation of the cells (6 days). Western blot analysis revealed that these functional changes correlate well with changes in the quantity of G(s)alpha, the stimulatory component of AC. Additional forskolin-induced adaptations were found for PGE1 receptors, inhibitory G proteins and AC. These data demonstrate that neuronal differentiation of NG108-15 cells is associated with complex regulatory changes within the stimulatory PGE1 receptor system.
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PMID:Regulation of stimulatory adenylyl cyclase signaling during forskolin-induced differentiation of mouse neuroblastoma x rat glioma (NG108-15) cells. 927 81

The cytoplasmic creatine kinase (CKB) enzyme has a central role in the regeneration of ATP in the brain. We have shown previously that CKB mRNA levels in cultured primary rat brain astrocytes and oligodendrocytes are much higher than in primary neurons. It has been suggested that high CKB expression is essential for the energy-demanding functions of glial cells. Conversely, CKB may be repressed in most neuronal cells; however, CKB protein has previously been detected by immunohistochemistry in several distinct groups of neurons in the adult rodent brain. Presently, little is known of the factors responsible for the high CKB expression in glia and possible repression in neurons. In this report, we investigated if low CKB mRNA was characteristic of some established neuronal cell lines. CKB mRNA was found to be extremely low in mouse C1300 neuroblastomas NS20Y and N1E-115 but 10-fold higher in NG108-15, a hybrid cell composed of a C1300 neuroblastoma and a rat C6 glioma. Since we showed NG108-15 contained only rat CKB mRNA transcribed from the C6 glioma CKB gene, expression of CKB mRNA may be a manifestation of a glial property in NG108-15 cells. However, CKB mRNA expression in NG108-15 appeared not to be fully activated since it was still 5-fold lower than in (parental) C6 glioma and 10-fold lower than in cellular RNA from either total rat brain or cultured primary astrocytes. When neuronal differentiation was increased in NS20Y and N1E-115 by treating cells with prostaglandin E1 and theophylline, the extremely low CKB mRNA level was not significantly changed. In a comparative study, the CKB mRNA levels in NS20Y, N1E-115 and neuronal RT4-B8 and RT4-E5 cells (from the rat RT4 peripheral neurotumor) were at least 50-fold lower than that in C6 glioma and 100-fold lower than in cultured primary astrocytes. These cell lines may provide a system for the identification of factors involved in the possible repression of CKB in many neuronal cells.
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PMID:Expression of the brain creatine kinase gene is low in neuroblastoma cell lines. 932 58

Phosducin (Phd), a cytosolic protein, has been proposed to compete with certain receptor kinases for Gbetagamma of heterotrimeric G proteins, and may inhibit GTPase activity of G alpha s. These suggestions together with the enhancing effect of Phd on odorant-induced cAMP accumulation let us assume a stimulatory action of the protein on intracellular signaling. Therefore, this investigation was designed to examine the excitatory effect of PGE1 on signal transmission in neuroblastoma x glioma hybrid cells (NG 108-15) overexpressing Phd. The neuronal cells stably expressing Phd were found to display a 3 to 4-fold increased sensitivity to PGE1 as compared to wild type cells, using cAMP accumulation as measure. Examination of membranes prepared from Phd-overexpressing cells revealed an elevated GTPase activity as indicated by the formation of 32Pi upon PGE1 challenge. This activity was inhibited by exogenous Phd. In addition, receptor independent stimulation of adenylate cyclase by forskolin reveals an increased formation of cAMP in Phd expressing cells, which is accompanied by an increased binding of [3H]forskolin. The findings let us propose that Phd elevates intracellular levels of functional G alpha s which accounts for the increased response to PGE1.
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PMID:Phosducin expression in NG 108-15 hybrid cells enhances prostaglandin E1 stimulated adenylate cyclase activity. 949 6

On the cellular level, opioid dependence is characterized by a significant elevation of adenylyl cyclase (AC) activity after drug withdrawal, a regulatory phenomenon termed "AC supersensitivity" or "cAMP overshoot." The present study examines the role of the stimulatory G protein (Gs) in the expression of naloxone precipitated opioid withdrawal in chronically morphine (10 microM; 3 days) treated neuroblastoma X glioma (NG108-15) hybrid cells. Determination of high-affinity [3H]forskolin binding to intact cells, which provides a direct parameter for the binding of the activated alpha-subunit of Gs (Gsalpha) to AC, revealed that the enhancement of AC activity after opioid withdrawal is not caused by an increased stimulation of effector activity by Gsalpha. Although not a direct function of Gs, the expression of AC supersensitivity required Gsalpha-mediated stimulation of AC, because 1) the enhancement of AC activity after opioid withdrawal was observed only in the presence of low, but not of high concentrations of forskolin, and 2) chemical inactivation of Gsalpha by low pH pretreatment abolished the induction of AC supersensitivity. Moreover, the regulatory mechanism underlying AC supersensitivity not only required the presence of activated Gsalpha per se, but functional intact stimulatory signal transduction pathways. Indeed, blockade of prostaglandin E1 receptor/Gs interaction in situ with a site-specific anti-Gsalpha antibody, as well as uncoupling of prostaglandin E1 receptor signaling by cholera toxin-catalyzed ADP-ribosylation of Gsalpha, prevented the expression of AC supersensitivity in membranes from opioid-withdrawn cells. These results suggest that the enhancement of AC activity in opioid-dependent cells, triggered by drug withdrawal, is not a direct Gsalpha effect, but involves a secondary regulatory event that requires costimulation of AC by acutely receptor-activated Gsalpha.
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PMID:Adenylyl cyclase supersensitivity in opioid-withdrawn NG108-15 hybrid cells requires Gs but is not mediated by the Gsalpha subunit. 969 42

Cellular mechanisms underlying the cognition-enhancing actions of piracetam-like nootropics were studied by recording Ca2+ channel currents from neuroblastoma x glioma hybrid (NG108-15) cells and Xenopus oocytes expressing Ca2+ channels. In NG108-15 cells, nefiracetam (1 microM) produced a twofold increase in L-type Ca2+ channel currents. A similar, but slightly less potent effect was observed with aniracetam, whereas piracetam and oxiracetam exerted no such effects. Cyclic AMP analogs mimicked the nefiracetam action. N-type Ca2+ channel currents inhibited by leucine (Leu)-enkephalin by means of inhibitory G proteins (Go/Gi) were recovered promptly by nefiracetam, whereas those inhibited by prostaglandin E1 via stimulatory G proteins were not affected by nefiracetam. Cells treated with pertussis toxin (500 ng/mL, > 20 hours) were insensitive to nefiracetam. In Xenopus oocytes functionally expressing N-type (alpha1B) Ca2+ channels and delta-opioid receptors, nefiracetam was also effective in facilitating the recovery from Leu-enkephalin-induced inhibition. These results suggest that nefiracetam, and possibly aniracetam, may activate N- and L-type Ca2+ channels in a differential way depending on how they recover from Go/Gi-mediated inhibition.
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PMID:Cellular mechanism of action of cognitive enhancers: effects of nefiracetam on neuronal Ca2+ channels. 1085 Jul 36

The aim of this study was to explore the effect of prostaglandin E1 (PGE1) on the membrane current of whole-cell voltage-clamped NG108-15 neuroblastoma x glioma hybrid cells. Perforated patch was used. The membrane current at -70 mV (leakage current) and the current-voltage curve produced by ramp pulses from -70 to 0 mV were recorded; from the I-V curve, the conductance of the leakage current and its reversal potential were determined. Bath application of PGE1 (22 nM-3 microM) produced an inward current accompanied by a reversible conductance increase. The PGE1 effect varied greatly from cell to cell. In a group of 11 differentiated cells, the inward current induced by 0.2 microM PGE1 was on average 171.1 +/- 49.8 pA, the conductance increased 2.66 +/- 0.50-fold and the reversal potential shifted by + 13.2 +/- 4.0 mV. The average values observed with 22 nM and 3 microM PGE1 were similar. The cell-permeable cAMP analog CPT-cAMP (0.5 mM) acted like PGE1. In 9 out of 16 cells, the PGE1 effect did not disappear and was not even noticeably reduced when the NaCl in the bath was replaced by N-methyl-D-glucamine (NMDG). The PGE1 effect was also seen in Ca2(+)-free NMDG bath but vanished when NMDG was replaced by glucose. It is concluded that PGE1, probably acting via intracellular cAMP, opens non-selective cation channels with large pore diameters which allow the passage of big organic cations.
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PMID:Prostaglandin El induces an inward current in voltage-clamped NG108-15 cells. 1451 66

Neurobiological actions of ethanol have been linked to perturbations in cyclic AMP (cAMP)-dependent signaling processes. Chronic ethanol exposure leads to desensitization of cAMP production in response to physiological ligands (heterologous desensitization). Ethanol-induced alterations in neuronal expression of G proteins G(s) and G(i) have been invoked as a cause of heterologous desensitization. However, effects of ethanol on G protein expression vary considerably among different experimental protocols, various brain regions and diverse neuronal cell types. Dynamic palmitoylation of G protein alpha subunits is critical for membrane localization and protein-protein interactions, and represents a regulatory feature of G protein function. We studied the effect of ethanol on G alpha(s) palmitoylation. In NG108-15 rat neuroblastoma x glioma hybrid cells, acute exposure to pharmacologically relevant concentrations of ethanol (25-100 mm) inhibited basal and prostaglandin E1-stimulated incorporation of palmitate into G alpha(s). Exposure of NG108-15 cells to ethanol for 72 h induced a shift in G alpha(s) to its non-palmitoylated state, coincident with an inhibition of prostaglandin E1-induced cAMP production. Both parameters were restored following 24 h of ethanol withdrawal. Chronic ethanol exposure also induced the depalmitoylation of G alpha(s) in human embryonic kidney (HEK)293 cells that overexpress wild-type G alpha(s) and caused heterologous desensitization of adenylyl cyclase. By contrast, HEK293 cells that express a non-palmitoylated mutant of G alpha(s) were insensitive to heterologous desensitization after chronic ethanol exposure. In summary, the findings identify a novel effect of ethanol on post-translational lipid modification of G alpha(s), and represent a mechanism by which ethanol might affect adenylyl cyclase activity.
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PMID:Ethanol inhibits palmitoylation of G protein G alpha(s). 1514 Jan 91

The aim of this study was to explore the effect of 0NO-54918-07, a stable prostacyclin analogue, on the current-voltage (IV) curve and the intracellular Ca2+ concentration [Ca2+]i of NG108-15 neuroblastoma x glioma hybrid cells. The IV curve was measured with ramp pulses from -70 to 0 mV, and [Ca2+]i was determined with Fura 2. Bath application of 0.2 muM ONO-54918-07 reversibly increased the holding current at -70 mV by -81.1 +/- 14.8 pA (mean +/- SEM, n = 35) and the slope of the IV curve between -70 and -50 mV by the factor 2.24 +/- 0.24. The effect of 0.2 microM prostaglandin PGE1 was similar (DeltaI (hold) = -96.1 +/- 29.9 pA, g/g (control) = 2.72 +/- 0.44, n = 9). ONO-54918-07 concentrations of 0.04, 2 and 6 microM were also effective. From the dose-response curve, the concentration for the half maximal effect was obtained as 0.054 microM. When cells did not respond to ONO-54918-07, an effect could sometimes be elicited by a ramp pulse or by a second ONO-54918-07 application 30-50 min after the first. The effect of ONO-54918-07 was not affected by pre-treatment with the EP1 antagonists ONO-8713 or SC-51089. However, a 14-40 min pre-treatment with 1 microM RO3244794, a selective prostacyclin receptor (IP) antagonist, abolished the effect of 0.2 microM PGE1. The effect of 0.2 microM ONO-54918-07 vanished completely in the presence of 5 microM RO32446794. ONO-54918-07 and PGE1 produced a slow increase in [Ca2+]i that lasted at least 6 min. Delta[Ca2+]i induced by both substances reached approximately 12% of the peak Delta[Ca2+]i induced by application of bradykinin. In only a few cells, PGE1 produced a brief, transient rise of [Ca2+]i. Using reverse transcriptase polymerase chain reaction, a prominent expression of the IP was detected in NG108-15 cells. It is concluded that ONO-54918-07 mimics the effect of PGE1, supporting the notion that the PGE1 effect on NG108-15 cells is mediated by IP receptors.
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PMID:ONO-54918-07, a stable prostacyclin analogue, mimics the effect of prostaglandin PGE1 on NG108-15 cells. 1795 10


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