Allosteric modulation of neurotoxin binding to voltage-sensitive sodium channels by Ptychodiscus brevis toxin 2.
The effects of Ptychodiscus brevis toxin 2 (PbTx-2) on the binding of neurotoxins at four different neurotoxin receptor sites on voltage-sensitive sodium channels in rat brain synaptosomes were examined. Binding of saxitoxin at neurotoxin receptor site 1 and Leiurus quinquestriatus alpha-scorpion toxin (LqTx) at neurotoxin receptor site 3 was unaffected. PbTx-2 enhanced binding of batrachotoxinin A 20-alpha-benzoate (BTX-B) to neurotoxin receptor site 2 and Centruroides suffusus suffusus beta-scorpion toxin (CsTx II) to site 4 on sodium channels. These results support the proposal that PbTx-2 and related toxins act at a new receptor site (site 5) that has not been previously analyzed in binding experiments. Half-maximal effects of PbTx-2 were observed in the range of 20-50 nM PbTx-2. The enhancement of BTX-B binding was reduced by depolarization. Saturating concentrations of PbTx-2 reduced KD values for binding of BTX-B and CsTx-II 2.9-fold and 2.6-fold, respectively. The effects of PbTx-2 and LqTx in enhancing BTX-B binding were synergistic. A model involving both preferential binding of BTX-B, PbTx-2, LqTx, and CsTx II to active states of sodium channels and allosteric interactions among the four receptor sites at which these toxins act accommodates these and previous results.
D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D001921:Brain; D004141:Dinoflagellida; D004357:Drug Synergism; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D008387:Marine Toxins / Q000378:metabolism* / Q000494:pharmacology*; D008564:Membrane Potentials; D009498:Neurotoxins / Q000378:metabolism*; D035964:Oxocins; D051381:Rats; D013574:Synaptosomes / Q000378:metabolism
D007473:Ion Channels; D008387:Marine Toxins; D009498:Neurotoxins; D035964:Oxocins; C051732:Ptychodiscus brevis T2 toxin