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Scorpion β-toxin interference with NaV channel voltage sensor gives rise to excitatory and depressant modes

Scorpion β-toxin interference with NaV channel voltage sensor gives rise to excitatory and... Scorpion β toxins, peptides of ∼70 residues, specifically target voltage-gated sodium (Na V ) channels to cause use-dependent subthreshold channel openings via a voltage–sensor trapping mechanism. This excitatory action is often overlaid by a not yet understood depressant mode in which Na V channel activity is inhibited. Here, we analyzed these two modes of gating modification by β-toxin Tz1 from Tityus zulianus on heterologously expressed Na V 1.4 and Na V 1.5 channels using the whole cell patch-clamp method. Tz1 facilitated the opening of Na V 1.4 in a use-dependent manner and inhibited channel opening with a reversed use dependence. In contrast, the opening of Na V 1.5 was exclusively inhibited without noticeable use dependence. Using chimeras of Na V 1.4 and Na V 1.5 channels, we demonstrated that gating modification by Tz1 depends on the specific structure of the voltage sensor in domain 2. Although residue G658 in Na V 1.4 promotes the use-dependent transitions between Tz1 modification phenotypes, the equivalent residue in Na V 1.5, N803, abolishes them. Gating charge neutralizations in the Na V 1.4 domain 2 voltage sensor identified arginine residues at positions 663 and 669 as crucial for the outward and inward movement of this sensor, respectively. Our data support a model in which Tz1 can stabilize two conformations of the domain 2 voltage sensor: a preactivated outward position leading to Na V channels that open at subthreshold potentials, and a deactivated inward position preventing channels from opening. The results are best explained by a two-state voltage–sensor trapping model in that bound scorpion β toxin slows the activation as well as the deactivation kinetics of the voltage sensor in domain 2. Submitted: 15 September 2011 Accepted: 5 March 2012 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of General Physiology Rockefeller University Press

Scorpion β-toxin interference with NaV channel voltage sensor gives rise to excitatory and depressant modes

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References (115)

Publisher
Rockefeller University Press
Copyright
© 2012 Leipold et al.
ISSN
0022-1295
eISSN
1540-7748
DOI
10.1085/jgp.201110720
pmid
22450487
Publisher site
See Article on Publisher Site

Abstract

Scorpion β toxins, peptides of ∼70 residues, specifically target voltage-gated sodium (Na V ) channels to cause use-dependent subthreshold channel openings via a voltage–sensor trapping mechanism. This excitatory action is often overlaid by a not yet understood depressant mode in which Na V channel activity is inhibited. Here, we analyzed these two modes of gating modification by β-toxin Tz1 from Tityus zulianus on heterologously expressed Na V 1.4 and Na V 1.5 channels using the whole cell patch-clamp method. Tz1 facilitated the opening of Na V 1.4 in a use-dependent manner and inhibited channel opening with a reversed use dependence. In contrast, the opening of Na V 1.5 was exclusively inhibited without noticeable use dependence. Using chimeras of Na V 1.4 and Na V 1.5 channels, we demonstrated that gating modification by Tz1 depends on the specific structure of the voltage sensor in domain 2. Although residue G658 in Na V 1.4 promotes the use-dependent transitions between Tz1 modification phenotypes, the equivalent residue in Na V 1.5, N803, abolishes them. Gating charge neutralizations in the Na V 1.4 domain 2 voltage sensor identified arginine residues at positions 663 and 669 as crucial for the outward and inward movement of this sensor, respectively. Our data support a model in which Tz1 can stabilize two conformations of the domain 2 voltage sensor: a preactivated outward position leading to Na V channels that open at subthreshold potentials, and a deactivated inward position preventing channels from opening. The results are best explained by a two-state voltage–sensor trapping model in that bound scorpion β toxin slows the activation as well as the deactivation kinetics of the voltage sensor in domain 2. Submitted: 15 September 2011 Accepted: 5 March 2012 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).

Journal

The Journal of General PhysiologyRockefeller University Press

Published: Apr 1, 2012

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