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)

Genetic elements involved in cell-specific expression of the type II sodium channel gene were revealed using transient expression assays. A chimeric reporter gene containing 1051 bp of the sodium channel 5' flanking region was active in neuroblastoma and PC12 cells, but inactive in nonneuronal cell types. Deletion of upstream sequences resulted in an 80-fold increase in reporter gene activity in skeletal muscle cells, suggesting the presence of negative elements. Although no homologies were found between sequences in the type II 5' flanking region and other negative elements or "silencers," a small region common to the type II gene and other genes expressed in the nervous system was identified and may be involved in transcriptional regulation of neuronal genes.
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PMID:Neuron-specific expression of the rat brain type II sodium channel gene is directed by upstream regulatory elements. 215 9

Single sodium channel events were recorded from cell-attached patches on single canine cardiac Purkinje cells at 10-13 degrees C. Data from four patches containing two to four channels and one patch with one channel were selected for quantitative analysis. The channels showed prominent reopening behavior at voltages near threshold, and the number of reopenings declined steeply with depolarization. Mean channel open time was a biphasic function of voltage with the maximum value (1-1.5 ms) occurring between -50 and -40 mV and lower values at more and at less hyperpolarized levels. Inactivation without opening was also prominent near threshold, and this occurrence also declined with depolarization. The waiting time distributions and the probability of being open showed voltage and time dependence as expected from whole-cell current studies. The results were analyzed in terms of a five-state Markovian kinetic model using both histogram analysis and a maximum likelihood method to estimate kinetic parameters. The kinetic parameters of the model fits were similar to those of GH3 pituitary cells (Horn, R., and C. A. Vandenberg. 1984. Journal of General Physiology. 84:505-534) and N1E115 neuroblastoma cells (Aldrich, R. W., and C. F. Stevens. Journal of Neuroscience. 7:418-431). Both histogram and maximum likelihood analysis implied that much of the voltage dependence of cardiac Na current is in its activation behavior, with inactivation showing modest voltage dependence.
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PMID:Kinetic analysis of single sodium channels from canine cardiac Purkinje cells. 215 91

1. The effects of chlorpromazine on the voltage-activated sodium and type I (transient) calcium channels were studied in cultured mouse neuroblastoma cells (N1E-115) using the whole-cell patch-clamp technique. 2. Chlorpromazine (2-10 x 10(-6) M) blocked both the sodium channel current and the calcium channel current as carried by Ba2+ in a reversible and dose-dependent manner. 3. The block was not associated with any change in the time course of the activation and inactivation of the sodium and calcium channel currents. 4. The dose-response relationships for the block of these channels measured with a holding potential of -120 mV indicated a 1:1 binding stoichiometry with apparent dissociation constants of 2.5 +/- 10(-6) M and 1.5 +/- 10(-5) M for the sodium and calcium channels, respectively. 5. The block was dependent on the holding potential for both channel currents. The apparent dissociation constant for the sodium channel was decreased to 0.65 +/- 10(-6) M when the membrane was held at -80 mV. The apparent dissociation constant for the calcium channel was decreased to 3.2 +/- 10(-6) M when the membrane was held at -60 mV. 6. The steady-state inactivation curve for the sodium channel was shifted by 12.4 +/- 1.8 mV to more negative potentials by exposure to 1 x 10(-6) M-chlorpromazine. The inactivation curve for the calcium channel was also shifted by 15.4 +/- 3.2 mV to more negative potentials by exposure to 1 x 10(-5) M-chlorpromazine. These results indicate a greater affinity of chlorpromazine for the inactivated state of the channels than for the resting state. 7. Chlorpromazine caused a marked use-dependent block of the sodium channel current, as demonstrated by a cumulative increase of the block during a train of depolarizing pulses. The use-dependent block was observed even with an interpulse interval as long as 2 s. 8. On the other hand, the block of the calcium channel current did not notably accumulate during a train of depolarizing pulses even when extremely prolonged (1 s) pulses were applied at a very short interpulse interval (200 ms). 9. The marked use dependence of the sodium channel block was due to a very slow repriming of the drug-bound sodium channels from inactivation, whereas the lack of use dependence of the calcium channel block was due to a rapid repriming of the drug-bound calcium channels.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential block of sodium and calcium channels by chlorpromazine in mouse neuroblastoma cells. 215 37

Pumiliotoxin B (PTX-B) and a variety of congeneric alkaloids and synthetic analogs stimulated sodium flux and phosphoinositide breakdown in guinea pig cerebral cortical synaptoneurosomes. The effects of PTX-B and active congeners and analogs on sodium flux in synaptoneurosomes were potentiated markedly by scorpion venom (Leiurus quinquestriatus). In neuroblastoma cells, PTX-B and active congeners had no effect on sodium flux unless synergized by alpha-scorpion toxin or scorpion venom. Certain inactive congeners, lacking hydroxyl groups in the 6-alkylidene side chain, inhibited sodium flux elicited by PTX-B, scorpion venom, or the sodium channel activator batrachotoxin. Such inhibition appeared different from inhibition by local anesthetics, since pumiliotoxins, unlike local anesthetics, had little or no effect on binding of [3H]batrachotoxinin A benzoate to sodium channels. Thus, it appears likely that some "inactive" congeners bind to the PTX-B binding site, but do not activate sodium channels. In the absence of scorpion venom the stimulation of phosphoinositide breakdown in synaptoneurosomes was consonant with the stimulatory effects of these compounds on sodium flux through voltage-dependent sodium channels.
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PMID:Pumiliotoxin alkaloids: a new class of sodium channel agents. 216 4

Measurements of neurotoxin-activated 22Na influx in neuroblastoma cells and neurotoxin binding in synaptosomes were used to define the site and mechanism of action of brevetoxins on sodium channels. Brevetoxin A alone did not enhance the sodium permeability of neuroblastoma cells, but markedly enhanced persistent activation of sodium channels by veratridine, aconitine and batrachotoxin, which act at neurotoxin receptor site 2. Enhancement of batrachotoxin action was accompanied by a 4.3-fold increase in the binding of [3H]batrachotoxinin A 20-alpha-benzoate to receptor site 2 on sodium channels in synaptosomes. These results point to an allosteric mechanism of brevetoxin action involving preferential binding to active states of sodium channels which have high affinity for neurotoxins, causing persistent activation of sodium channels at receptor site 2. Brevetoxin A does not block [3H]saxitoxin binding at neurotoxin receptor site 1 or 125I-labeled scorpion toxin binding at neurotoxin receptor site 3. The brevetoxins appear to act at a new neurotoxin receptor site on the sodium channel.
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PMID:Interaction of brevetoxin A with a new receptor site on the sodium channel. 241 Oct 17

The saxitoxin binding properties and sodium currents were compared in N18 neuroblastoma cells grown in serum-supplemented and chemically defined serum-free media. There was no alteration in either maximal binding capacity or receptor affinity and the kinetics or voltage dependency of sodium channel activation and inactivation. It is concluded that sodium channels expressed by neuroblastoma cells grown in the chemically defined media were functionally identical to those in cells grown in serum-supplemented medium.
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PMID:Properties of voltage-sensitive sodium channels in neuroblastoma cells grown in chemically defined and serum-supplemented media. 241 58

Goniopora toxin (GPT), a polypeptide toxin of 9700 Da isolated from coral, markedly slows inactivation of sodium currents recorded under voltage clamp in mouse neuroblastoma cells. The voltage dependence of sodium channel activation is shifted to more negative membrane potentials by 9.8 +/- 2.1 mV, and the voltage dependence of channel inactivation is shifted to more positive membrane potential by 6.0 +/- 2.5 mV. These actions of GPT are voltage dependent with an e-fold increase in K0.5 for toxin action for each 48.3-mV depolarization between -80 and +40 mV. GPT requires Na+ or another alkali metal cation in the extracellular medium for its effect on sodium channels. The relative effectiveness of the different cations tested is Na+ greater than K+ greater than Rb+ greater than Li+ greater than Cs+ much greater than choline+. Like other polypeptide neurotoxins that slow inactivation of sodium channels, GPT enhances persistent activation of sodium channels by veratridine. However, GPT does not block the binding of 125I-labeled Leiurus scorpion toxin to neurotoxin receptor site 3 on sodium channels at concentrations which effectively slow channel inactivation. Therefore, our results define a new site on the sodium channel at which specific effects on inactivation can occur.
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PMID:Mechanism of action of a polypeptide neurotoxin from the coral Goniopora on sodium channels in mouse neuroblastoma cells. 242 33

Certain antiepileptic drugs are known to block sodium and calcium channels of excitable membranes. These channels are responsible for generation of action potentials. Various natural toxins, chemicals, and therapeutic drugs have been found to modify the gating kinetics of the sodium and/or calcium channels, thereby altering the excitation. Studies of such chemical modulations of the sodium and calcium channel gating provide the basis for understanding the mechanisms underlying epilepsies and the actions of antiepileptic drugs. Tetrodotoxin blocks the sodium channels, whereas batrachotoxin (BTX), grayanotoxin (GTX), and pyrethroids modify a population of the sodium channels to give rise to an extremely slow opening and/or closing. Patch-clamp techniques developed during the past few years permit measurements of opening and closing of individual ionic channels. When a membrane patch isolated from a neuroblastoma cell is depolarized, square inward currents of about 1 pA in amplitude and 2 msec in duration are observed at 10 degrees C. After exposure of the membrane to BTX, the open time is prolonged, the single-current amplitude is reduced, and channel opening is observed at large negative potentials at which no opening is expected to occur in normal preparations. In the BTX-poisoned membrane, there are two separate groups of the sodium channels, one exhibiting the normal characteristics and the other exhibiting a prolonged opening and reduced amplitude. Tetramethrin also modifies the single sodium channel in a similar manner to BTX, but fails to affect the amplitude of single-channel current. Neuroblastoma cells are also endowed with calcium channels, which undergo inactivation in a manner dependent upon membrane potential.
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PMID:Modulators acting on sodium and calcium channels: patch-clamp analysis. 242 92

We studied the dose-response relationship between gamma radiation and batrachotoxin-stimulated sodium influx in neuroblastoma cells in tissue culture. We also tested the hypothesis that changes in sodium channel conformation may alter the radiosensitivity of the channel. We found that gamma radiation inhibited toxin-stimulated 22Na uptake at doses beyond a threshold of 200-300 Gy. No effects were seen following doses below 100 Gy. This inhibition of sodium permeability was seen when the cells were irradiated with sodium channels in the closed or inactivated, nonconducting states. However, when the channels were in the toxin-opened, conducting state, gamma radiation had no effect at doses up to 2000 Gy. Our results support earlier electrophysiological studies that showed that high doses of ionizing radiation are required to produce a measurable decrease in sodium permeability. In addition, our data suggest that by changing the sodium channel conformation, batrachotoxin appears to alter radiosensitive chemical bonds in the gating or ion-conducting portion of the channel.
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PMID:Effect of gamma radiation on sodium channels in different conformations in neuroblastoma cells. 242 30

Certain natural toxins and environmental agents have been found to act on nerve membrane ionic channels in a highly specific manner. For example, the puffer fish poison, tetrodotoxin, blocks the sodium channel without affecting its gating mechanism. The sodium channel is also the major target site of the pyrethroid and DDT insecticides. Patch clamp single channel recording experiments with cultured neuroblastoma cells have revealed that individual sodium channels are kept open much longer in the presence of the pyrethroid tetramethrin than in control. This effect accounts for a marked prolongation of sodium current by tetramethrin observed in giant axons. The prolonged sodium current increases the depolarizing after-potential which in turn generates repetitive after-discharges. The symptoms of pyrethroid poisoning in animals can be explained on this basis. Only a very small fraction of sodium channels, less than 1%, needs to be modified by pyrethroids to produce the symptoms of poisoning. Fenvalerate, a cyano-containing type II pyrethroid, prolongs the sodium channel open time much more drastically than tetramethrin. This causes a persistent depolarization of the membrane, which in turn blocks conduction.
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PMID:Nerve membrane ionic channels as the target of toxicants. 243 60


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