Pyrethroids and voltage sensors in sodium channels

α-Scorpion Toxin Impairs a Conformational Change that Leads to Fast Inactivation of Muscle Sodium Channels

The Journal of General Physiology ◽

10.1085/jgp.200809995 ◽

2008 ◽

Vol 132 (2) ◽

pp. 251-263 ◽

Cited By ~ 71

Author(s):

Fabiana V. Campos ◽

Baron Chanda ◽

Paulo S.L. Beirão ◽

Francisco Bezanilla

Keyword(s):

Sodium Channels ◽

Slow Component ◽

Scorpion Toxin ◽

Fast Inactivation ◽

Gating Current ◽

Voltage Sensors ◽

Current Decay ◽

Fluorescence Measurements ◽

Gating Charge ◽

Domain Iii

α-Scorpion toxins bind in a voltage-dependent way to site 3 of the sodium channels, which is partially formed by the loop connecting S3 and S4 segments of domain IV, slowing down fast inactivation. We have used Ts3, an α-scorpion toxin from the Brazilian scorpion Tityus serrulatus, to analyze the effects of this family of toxins on the muscle sodium channels expressed in Xenopus oocytes. In the presence of Ts3 the total gating charge was reduced by 30% compared with control conditions. Ts3 accelerated the gating current kinetics, decreasing the contribution of the slow component to the ON gating current decay, indicating that S4-DIV was specifically inhibited by the toxin. In addition, Ts3 accelerated and decreased the fraction of charge in the slow component of the OFF gating current decay, which reflects an acceleration in the recovery from the fast inactivation. Site-specific fluorescence measurements indicate that Ts3 binding to the voltage-gated sodium channel eliminates one of the components of the fluorescent signal from S4-DIV. We also measured the fluorescent signals produced by the movement of the first three voltage sensors to test whether the bound Ts3 affects the movement of the other voltage sensors. While the fluorescence–voltage (F-V) relationship of domain II was only slightly affected and the F-V of domain III remained unaffected in the presence of Ts3, the toxin significantly shifted the F-V of domain I to more positive potentials, which agrees with previous studies showing a strong coupling between domains I and IV. These results are consistent with the proposed model, in which Ts3 specifically impairs the fraction of the movement of the S4-DIV that allows fast inactivation to occur at normal rates.

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Targeting voltage sensors in sodium channels with spider toxins

Trends in Pharmacological Sciences ◽

10.1016/j.tips.2009.12.007 ◽

2010 ◽

Vol 31 (4) ◽

pp. 175-182 ◽

Cited By ~ 100

Author(s):

Frank Bosmans ◽

Kenton J. Swartz

Keyword(s):

Sodium Channels ◽

Voltage Sensors ◽

Spider Toxins

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β-Scorpion Toxin Modifies Gating Transitions in All Four Voltage Sensors of the Sodium Channel

The Journal of General Physiology ◽

10.1085/jgp.200609719 ◽

2007 ◽

Vol 130 (3) ◽

pp. 257-268 ◽

Cited By ~ 58

Author(s):

Fabiana V. Campos ◽

Baron Chanda ◽

Paulo S.L. Beirão ◽

Francisco Bezanilla

Keyword(s):

Sodium Channel ◽

Sodium Channels ◽

Integrated Approach ◽

Voltage Sensor ◽

Scorpion Toxin ◽

Charge Voltage ◽

Voltage Sensors ◽

Fluorescence Measurements ◽

Voltage Gated Sodium Channels ◽

Activated State

Several naturally occurring polypeptide neurotoxins target specific sites on the voltage-gated sodium channels. Of these, the gating modifier toxins alter the behavior of the sodium channels by stabilizing transient intermediate states in the channel gating pathway. Here we have used an integrated approach that combines electrophysiological and spectroscopic measurements to determine the structural rearrangements modified by the β-scorpion toxin Ts1. Our data indicate that toxin binding to the channel is restricted to a single binding site on domain II voltage sensor. Analysis of Cole-Moore shifts suggests that the number of closed states in the activation sequence prior to channel opening is reduced in the presence of toxin. Measurements of charge–voltage relationships show that a fraction of the gating charge is immobilized in Ts1-modified channels. Interestingly, the charge–voltage relationship also shows an additional component at hyperpolarized potentials. Site-specific fluorescence measurements indicate that in presence of the toxin the voltage sensor of domain II remains trapped in the activated state. Furthermore, the binding of the toxin potentiates the activation of the other three voltage sensors of the sodium channel to more hyperpolarized potentials. These findings reveal how the binding of β-scorpion toxin modifies channel function and provides insight into early gating transitions of sodium channels.

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