The study proposes a model where activation does not require complete movement of segment S4 of domain IV, but a more extensive movement is needed for normal fast inactivation.
No immediate clinical implications from this animal model; leaves open refined gating mechanisms for future channel-targeted research.
The voltage-dependent displacement of the scorpion Tityus serrulatus alpha-toxin Ts3 was investigated in native sodium channels of GH3 cells by examining the removal of its effects in toxin-free solution. Toxin at saturating concentration was pulsed (approximately 1 s) directly onto the cell, thus causing an eight-fold increase of the slow component (taus = 6 ms) of fast inactivation, and a three-fold increase of the time constant of its fast component. At 0 mV, maximal conductance was achieved in cells before and after treatment with Ts3, and no displacement of the toxin could be detected. Toxin displacement occurred if stronger depolarising pulses (> 100 mV) were applied. The rate of displacement depended on the amplitude and duration of the pulses, and was not related with outward Na+ flux. We propose a model in which activation does not require complete movement of segment S4 of domain IV (IVS4) and that a more extensive movement of this segment is needed for normal fast inactivation. A kinetic model is presented that can account for the typical effects of site 3 toxins.
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Campos et al. (2004) studied this question.
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