Interaction of scorpion alpha-toxins with cardiac sodium channels: Bindingproperties and enhancement of slow inactivation

The effects of the scorpion alpha -toxins Lqh II, Lqh III, and Lqh alpha IT on human cardiac sodium channels (hH1), which were expressed in human embr yonic kidney (HEK) 293 cells, were investigated. The toxins removed fast in activation with EC50 Values of <2.5 nM (Lqh III), 12 nM (Lqh II), and 33 nM (Lqh alpha IT). Association and dissociation rates of Lqh III were much sl ower than those of Lqh II and Lqh alpha IT, such that Lqh III would not dis sociate from the channel during a cardiac activation potential. The voltage dependence of toxin dissociation from hi-II channels was nearly the same f or all toxins tested, but it nas different from that found for skeletal mus cle sodium channels (muI; Chen et al., 2000). These results indicate that t he voltage dependence of toxin binding is a property of the channel protein . Toxin dissociation remained voltage dependent even at high voltages where activation and fast inactivation is saturated, indicating that the voltage dependence originates from other sources. Slow inactivation of hH1 and muI channels was significantly enhanced by Lqh II and Lqh III. The half-maxima l voltage of steady-state slow inactivation was shifted to negative values, the voltage dependence was increased, and, in particular for hH1, slow ina ctivation at high voltages became more complete. This effect exceeded an ex pected augmentation of slow inactivation owing to the loss of fast inactiva tion and, therefore, shows that slow sodium channel inactivation may be dir ectly modulated by scorpion a-toxins.