Inactivated state dependence of sodium channel modulation by beta-scorpiontoxin

We have examined the effects of a beta-scorpion toxin purified from the ven om of the Venezuelan scorpion Tityus discrepans, TdVIII, on heterologously expressed rat skeletal muscle Na+ channels (rSkM1). TdVIII (100 nM) produce d a leftward shift in the voltage dependence of activation and reduced the peak Na+ conductance of rSkM1 channels coexpressed with the rat brain beta 1 subunit in Xenopus laevis oocytes, suggesting that TdVIII is a beta-scorp ion toxin. These effects did not depend on the presence of the beta 1 subun it. Modification of rSkM1 activation by TdVIII could be augmented by increa sing the rate of stimulation (enhanced use-dependence). Shifts in channel a ctivation were also enhanced by introducing conditioning pulses to -10 mV, and this enhancement increased with conditioning pulse duration. On the oth er hand, TdVIII did not affect the activation of fast-inactivation deficien t mutant Na+ channels, I1303Q/F1304Q/M1305Q. These results suggest that mod ulation of rSkM1 Na+ channel gating by TdVIII depends on the toxin interact ing with the inactivated state of the alpha subunit.