State-dependent access to the batrachotoxin receptor on the sodium channel.
Batrachotoxin causes sustained opening of voltage-gated sodium channels. Toxin binds irreversibly to wild type channels; however, it dissociates rapidly from channels with mutation F1710C in transmembrane segment IVS6. This dissociation requires channel activation, suggesting that the activation gate guards the toxin-binding site. Here we show that activity-dependent toxin dissociation was not affected by external sodium, arguing against a binding site within the pore, and demonstrate that dissociation occurred only during the first few milliseconds after membrane depolarization, as if the toxin leaves its binding site during closed states that precede the final open state in the activation pathway. Toxin interaction with preopen states may facilitate subsequent channel opening, thus accounting for the batrachotoxin-induced negative shift in channel activation.
De Leon
Lyn
L
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
Ragsdale
David S
DS
D000818:Animals; D001496:Batrachotoxins / Q000494:pharmacology*; D001665:Binding Sites / Q000502:physiology; D003545:Cysteine / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004553:Electric Conductivity; D004558:Electric Stimulation; D005110:Extracellular Space; D005260:Female; D008564:Membrane Potentials / Q000187:drug effects; D016297:Mutagenesis, Site-Directed; D009865:Oocytes; D010599:Pharmacokinetics; D010649:Phenylalanine / Q000235:genetics; D017434:Protein Structure, Tertiary; D051381:Rats; D012964:Sodium / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D014981:Xenopus
D001496:Batrachotoxins; D015222:Sodium Channels; C041417:batrachotoxin receptor; D010649:Phenylalanine; D012964:Sodium; D003545:Cysteine