Natural products from ginseng inhibit [3H]batrachotoxinin A 20-alpha-benzoate binding to Na+ channels in mammalian brain.
A [(3)H]batrachotoxinin A-20alpha-benzoate ([(3)H]BTX-B) binding assay was used to investigate the interaction of two ginseng aglycones (20(S)protopanaxadiol and 20(S)protopanaxatriol) and Rh(2) (a monoglucoside of 20(S)protopanaxadiol) with voltage-gated sodium channels in mouse brain. All compounds inhibited the binding of [(3)H]BTX-B and IC(50)s were established at 42 microM (20(S)protopanaxadiol), 79 microM (20(S)protopanaxatriol) and 162 microM (Rh(2)). Scatchard analysis confirmed that 20(S)protopanaxadiol and Rh-2 reduced the B(max) of [(3)H]BTX-B binding while Rh(2) also increased the K(d). At IC(50) concentrations and above, 20(S)protopanaxadiol and Rh(2) increased the dissociation of the [(3)H]BTX-B:sodium channel complex above that produced by a saturating concentration of veratridine, but failed to reduce the rate of association of [(3)H]BTX-B with sodium channels. Reversal of the inhibition of [(3)H]BTX-B binding by 20(S)protopanaxadiol and Rh(2) occurred slowly. We conclude that the 20(S)protopanaxadiol and the less potent inhibitor Rh(2) destabilize BTX-B-activated sodium channels through non-covalent allosteric modification of neurotoxin binding site 2.
Duan
Yin
Y
Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
Zheng
Jian
J
Law
Vanessa
V
Nicholson
Russell
R
D000818:Animals; D001496:Batrachotoxins / Q000378:metabolism*; D001667:Binding, Competitive / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D036145:Ginsenosides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D005894:Panax / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011869:Radioligand Assay; D012502:Sapogenins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism*; D012995:Solubility; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D014316:Tritium
D001496:Batrachotoxins; D036145:Ginsenosides; D010936:Plant Extracts; D012502:Sapogenins; D015222:Sodium Channels; D014315:Triterpenes; D014316:Tritium; C081552:protopanaxatriol; C055305:ginsenoside Rh2; C031775:batrachotoxinin A 20-alpha-benzoate; C062916:protopanaxadiol