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