title: Open- and closed-state fast inactivation in sodium channels: differential effects of a site-3 anemone toxin.
abstract: The role of sodium channel closed-state fast inactivation in membrane excitability is not well understood. We compared open- and closed-state fast inactivation, and the gating charge immobilized during these transitions, in skeletal muscle channel hNa(V)1.4. A significant fraction of total charge movement and its immobilization occurred in the absence of channel opening. Simulated action potentials in skeletal muscle fibers were attenuated when pre-conditioned by sub-threshold depolarization. Anthopleurin A, a site-3 toxin that inhibits gating charge associated with the movement of DIVS4, was used to assess the role of this voltage sensor in closed-state fast inactivation. Anthopleurin elicited opposing effects on the gating mode, kinetics and charge immobilized during open- versus closed-state fast inactivation. This same toxin produced identical effects on recovery of channel availability and remobilization of gating charge, irrespective of route of entry into fast inactivation. Our findings suggest that depolarization promoting entry into fast inactivation from open versus closed states provides access to the IFMT receptor via different rate-limiting conformational translocations of DIVS4.
authors.affiliation: Department of Biological Sciences, Idaho State University, Pocatello, USA. groojame@isu.edu
authors.forename: James
authors.initials: J
authors.lastname: Groome
authors.forename: Frank
authors.initials: F
authors.lastname: Lehmann-Horn
authors.forename: Boris
authors.initials: B
authors.lastname: Holzherr
mesh_terms: D000200:Action Potentials; D000818:Animals; D003064:Cnidarian Venoms / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D009124:Muscle Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D062553:NAV1.4 Voltage-Gated Sodium Channel; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D012615:Sea Anemones; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014981:Xenopus
chemical_list: D003064:Cnidarian Venoms; D036341:Intercellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; D010455:Peptides; C106251:SCN4A protein, human; C466180:Scn4a protein, rat; D015222:Sodium Channels; D013779:Tetrodotoxin; C012746:anthopleurin-A; D012964:Sodium