title: Evidence for multiple effects of ProTxII on activation gating in Na(V)1.5.
abstract: The peptide toxin ProTxII, recently isolated from the venom of the tarantula spider Thrixopelma pruriens, modifies gating in voltage-gated Na+ and Ca2+ channels. ProTxII is distinct from other known Na+ channel gating modifier toxins in that it affects activation, but not inactivation. It shifts activation gating positively and decreases current magnitude such that the dose-dependence of toxin action measured at a single potential reflects both effects. To test the extent to which these effects were independent, we tracked several different measures of current amplitude, voltage-dependent activation, and current kinetics in Na(V)1.5 in a range of toxin concentrations. Changes in voltage dependence and a decrease in G(max) appeared at relatively low concentrations (40-100 nM) while a positive shift in the voltage range of activation was apparent at higher toxin concentrations (> or =500 nM). Because ProTxII carries a net +4 charge we tested whether electrostatic interactions contributed to toxin action. We examined the effects of ProTxII in the presence of high extracellular Ba2+, known to screen and/or bind to surface charge. Some, but not all aspects of ProTxII modification were sensitive to the presence of Ba2+ indicating the contribution of an electrostatic, surface charge-like mechanism and supporting the idea of a multi-faceted toxin-channel interaction.
authors.affiliation: Committee on Neurobiology, University of Chicago, 5841 South Maryland Avenue, MC6094, Chicago, IL 60637, USA.
authors.forename: Gabrielle B
authors.initials: GB
authors.lastname: Edgerton
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Blumenthal
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Hanck
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013111:Spider Venoms / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013112:Spiders / Q000502:physiology
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C470626:ProTx-II peptide; C568320:SCN5A protein, human; D015222:Sodium Channels; D013111:Spider Venoms