DIFFERENTIAL-EFFECTS OF SULFHYDRYL-REAGENTS ON SAXITOXIN AND TETRODOTOXIN BLOCK OF VOLTAGE-DEPENDENT NA CHANNELS

We have probed a cysteine residue that confers resistance to tetrodoto xin (TTX) block in heart Na channels, with membrane-impermeant, cystei ne-specific, methanethiosulfonate (MTS) analogs. Covalent addition of a positively charged group to the cysteinyl sulfhydryl reduced pore co nductance by 87%. The effect was selectively prevented by treatment wi th TTX, but not saxitoxin (STX). Addition of a negatively charged grou p selectively inhibited STX block without affecting TTX block. These r esults agree with models that place an exposed cysteinyl sulfhydryl in the TTX site adjacent to the mouth of the pore, but do not support th e contention that STX and TTX are interchangeable. The surprising diff erences between the two toxins are consistent with the hypothesis that the toxin-receptor complex can assume different conformations when ST X or TTX bound.