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 alkaloid pumiliotoxin B (PTX-B) "activates" voltage-dependent sodium channels in synaptoneurosomes and neuroblastoma cells. It appears that PTX-B activates sodium channels by interacting with a site that is allosterically coupled to other sites on the sodium channel, namely two scorpion toxin sites and the brevetoxin site. In guinea pig cortical synaptoneurosomes, alpha-scorpion toxin, beta-scorpion toxin, and brevetoxin induce a dose-dependent potentiation of PTX-B-induced 22Na+ influx. The synergism with beta-scorpion toxin differentiates PTX-B from the alkaloid veratridine, which induces an activation of sodium channels that is not affected by beta-scorpion toxin. PTX-B does not inhibit [3H]batrachotoxinin-A benzoate ([3H]BTX-B) binding to the alkaloid site on sodium channels. On the other hand, aconitine, which activates sodium channels and inhibits [3H]BTX-B binding, induces a 22Na+ influx that, like PTX-B-induced 22Na+ influx, is potentiated by alpha-scorpion toxin, beta-scorpion toxin, and brevetoxin. Inhibition of [3H]BTX-B binding by aconitine is reduced in the presence of PTX-B. Both a type I pyrethroid (allethrin) and a type II pyrethroid (fenvalerate) inhibit PTX-B- and PTX-B/alpha-scorpion toxin-mediated 22Na+ influx. Allethrin and fenvalerate also inhibit aconitine-mediated 22Na+ flux but not BTX-mediated 22Na+ influx. It is proposed that on the sodium channel there is an "alkaloid-binding domain" at which alkaloids exert stimulatory actions. However, depending on the region on the domain to which the binding occurs, different allosteric interactions with other sites can be observed. PTX-B is proposed to interact with a part of the alkaloid-binding domain that is shared by aconitine but not by batrachotoxin or veratridine, whereas aconitine interacts with a part of the domain shared by PTX-B and by batrachotoxin/veratridine.
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PMID:Interaction of pumiliotoxin B with an "alkaloid-binding domain" on the voltage-dependent sodium channel. 133 16

1. Prolongation of action potentials by cooling or pharmacological treatment can restore conduction in demyelinated axons. We have assessed the ability of pyrethroids (in vitro) to modify action potential kinetics and to reverse conduction block in lesioned peripheral nerve. 2. Fast Na+ currents were isolated in mammalian neuroblastoma (NIE115). Pyrethroids (4 microM) concurrently slowed inactivation and produced a spectrum of pronounced tail currents: s-bioallethrin (duration 12.2+/-7 ms), permethrin (24.2+/-3 ms) and deltamethrin (2230+/-100 ms). 3. Deltamethrin (5 microM) effected a slowly developing depression of compound action potential (CAP) amplitude in peroneal nerve trunks (P<0.05). Permethrin produced no net effect on CAP amplitude, area or repolarization time. 4. s-Bioallethrin (5 microM) enhanced CAP area, time for 90% repolarization and induced regenerative activity in a subpopulation of axons. 5. Tibial nerve trunks were demyelinated by lysolecithin (2 micro1) injection: 6-14 days later, slowly-conducting axons in the CAP (and peri-axonal microelectrode recordings) were selectively blocked by warming to 37 degrees C. 6. At 37 degrees C, s-bioallethrin (45 min, 5 microM) produced much greater after-potentials in lesioned nerves than in uninjected controls: area (P< 0.05) and relative amplitude ratios (P< 0.0001) were significantly altered. 7. In 3 of 4 cells (single-unit recording), s-bioallethrin restored conduction through axons exhibiting temperature-dependent block by raising blocking temperature (by 1.5 to > 3 degrees C) and reducing refractory period. 8. s-Bioallethrin induced temperature-dependent regenerative activity only in a sub-population of axons even after prolonged superfusion (> 1 h). 9. It was concluded that pyrethroids differentially alter Na+ current kinetics and action potential kinetics. The effects of s-bioallethrin are consistent with reversal of conduction block by demyelinated axons but regenerative/ectopic firing even in normal cells is likely to underpin its acknowledged neurotoxic actions and severely limit the clinical potential of this and related molecules.
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PMID:Effects of pyrethroid molecules on rat nerves in vitro: potential to reverse temperature-sensitive conduction block of demyelinated peripheral axons. 950 90