Chemical modification reduces the conductance of sodium channels in nerve

Tetrodotoxin (TTX) and saxitoxin (STX) are extremely potent poisons that prevent nerve and muscle cells from producing action potentials by blocking sodium channels. If the channels are modified by reagents that act on carboxyl groups, however, both the binding of these toxins and their effect on the action potential are reduced. One such reagent, trimethyloxonium ion (TMO) converts channels into a form that is not blocked by TTX concentrations 10(5) times greater than its normal Kd (ref. 6). Most such chemical modifications of sodium channels also reduce the measured membrane sodium current, but it has not been known whether such reductions were due to a change in the number of channels, in permeability properties, or in gating properties. We now report that TMO-modified, TTX-resistant sodium channels have a smaller single-channel conductance (gamma) with a more linear instantaneous current-voltage relationship than that of normal channels, and that the measured reduction in gamma accounts for all of the decrease in sodium current after TMO treatment. This change in sodium channel permeability properties can be explained by the removal of a fixed negative charge near the outside of the channel.