title: Modulation of human Nav1.7 channel gating by synthetic α-scorpion toxin OD1 and its analogs.
abstract: Nine different voltage-gated sodium channel isoforms are responsible for inducing and propagating action potentials in the mammalian nervous system. The Nav1.7 channel isoform plays an important role in conducting nociceptive signals. Specific mutations of this isoform may impair gating behavior of the channel resulting in several pain syndromes. In addition to channel mutations, similar or opposite changes in gating may be produced by spider and scorpion toxins binding to different parts of the voltage-gated sodium channel. In the present study, we analyzed the effects of the α-scorpion toxin OD1 and 2 synthetic toxin analogs on the gating properties of the Nav1.7 sodium channel. All toxins potently inhibited channel inactivation, however, both toxin analogs showed substantially increased potency by more than one order of magnitude when compared with that of wild-type OD1. The decay phase of the whole-cell Na(+) current was substantially slower in the presence of toxins than in their absence. Single-channel recordings in the presence of the toxins revealed that Na(+) current inactivation slowed due to prolonged flickering of the channel between open and closed states. Our findings support the voltage-sensor trapping model of α-scorpion toxin action, in which the toxin prevents a conformational change in the domain IV voltage sensor that normally leads to fast channel inactivation.
authors.affiliation: a Health Innovations Research Institute, RMIT University , Melbourne , Victoria, Australia.
authors.forename: Leonid
authors.initials: L
authors.lastname: Motin
authors.affiliation: b Division of Chemistry & Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane , Queensland, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Durek
authors.affiliation: a Health Innovations Research Institute, RMIT University , Melbourne , Victoria, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D015870:Gene Expression; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects*; D009154:Mutation; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D000072417:Protein Domains; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012604:Scorpion Venoms / Q000138:chemical synthesis / Q000494:pharmacology*; D012605:Scorpions; D012964:Sodium / Q000378:metabolism*
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C514165:OD1 toxin, Odonthobuthus doriae; D011994:Recombinant Proteins; C486866:SCN9A protein, human; D012604:Scorpion Venoms; D012964:Sodium
keywords: Nav1.7; gating; patch clamp; scorpion toxin; voltage-gated sodium channel