Tityustoxin-Kα, a structurally novel and highly potent K⁺ channel peptide toxin, interacts with the α-dendrotoxin binding site on the cloned Kv1.2 K⁺ channel

The interaction between two nonhomologous K⁺ channel toxins, Tityus serrulatus (scorpion) toxin tityustoxin-Kα (TsTX-Kα) and Dendroaspis angusticeps (snake) toxin dendrotoxin (α-DTX), was investigated on K⁺ currents in B82 fibroblast cells transformed to express the Kv1.2 K⁺ channel. As demonstrated previously, α-DTX was a potent blocker of the K⁺ current (K_d, 2.8 nM). Recombinant TsTX-Kα produced a similar block of the current but was 1 order of magnitude more potent (K_d, 0.21 nM). TsTX-Kα did not affect the kinetic properties of the current or its voltage dependence of activation. Experiments with excised and cell-attached patch recordings demonstrated that TsTX-Kα blocks the K⁺ channel by binding to an extracellular site. In the presence of TsTX-Kα the blocking potency of α-DTX was reduced, whereas the potency of 4-aminopyridine, which also blocks the channel, was unaffected. α-DTX caused a rightward shift in the scaled concentration-response curve for TsTX-Kα, the magnitude of which was reasonably well predicted by a model in which there is a competitive interaction between the two peptide toxins. We conclude that TsTX-Kα and α-DTX block the Kv1.2 K⁺ channel by binding to the same or closely related sites.