Activation of sodium channels and inhibition of [3H]batrachotoxinin A-20-α-benzoate by an N-alkylamide neurotoxin
Document Type
Article
Publication Date
1-1-1989
Abstract
BTG 502 [(2E,4E)-N-(1,2-dimethyl)-propyl-6-(5-bromonaphth-2-yl)-hexa-2,4- dienamide], a synthetic analog of insecticidal amides isolated from Piper species, stimulated 22Na+ uptake into mouse brain synaptoneurosomes in the presence of saturating concentrations of Leiurus quinquestriatus venom but had no effect on sodium uptake in the absence of venom. In the presence of Leiurus venom, half-maximal stimulation was achieved at a BTG 502 concentration of 1.7 μM, whereas maximal stimulation (2.3-fold greater than nonspecific uptake) was observed at 50 μM. In the absence of other modifiers, BTG 502 inhibited batrachotoxin (BTX)-dependent sodium uptake, producing 50% inhibition at 2 μM. In the presence of Leiurus venom, BTG 502 was a partial inhibitor of BTX-dependent 22Na+ uptake, producing half-maximal inhibition at 1.5 μM. The levels of residual BTX-dependent sodium uptake and maximal BTG 502-dependent sodium uptake measured in the presence of Leiurus venom were identical. BTG 502 inhibited the specific binding of [3H]batrachotoxinin A-20-α-benzoate (BTX-B) to the activator recognition site (site 2) of sodium channels in these prearations, producing half-maximal inhibition at 2 μM and maximal inhibition at 30 μM. Equilibrium analysis showed that BTG 502 was an apparent competitive inhibitor of [3H]BTX-B binding, producing a concentration-dependent decrease in the affinity of sodium channels for this ligand without affecting binding capacity. Kinetic analysis demonstrated that BTG 502 slowed the rate of formation of the ligand-receptor complex but did not alter the rate of dissociation of this complex. The effects of BTG 502 on 22Na+ uptake and [3H]BTX-B binding are consistent with the action of this compound as an antagonist channel in the absence of Leiurus venom and as a partial agonist at this site in the presence of Leiurus venom. These results suggest that the N-alkylamides represent a novel chemical class of neurotoxins that act at site 2 of the sodium channel.
Publication Source (Journal or Book title)
Molecular Pharmacology
First Page
280
Last Page
284
Recommended Citation
Ottea, J., Payne, G., Bloomquist, J., & Soderlund, D. (1989). Activation of sodium channels and inhibition of [3H]batrachotoxinin A-20-α-benzoate by an N-alkylamide neurotoxin. Molecular Pharmacology, 36 (2), 280-284. Retrieved from https://repository.lsu.edu/entomology_pubs/1072