TITYUSTOXIN-K-ALPHA, A STRUCTURALLY NOVEL AND HIGHLY POTENT-K-DENDROTOXIN BINDING-SITE ON THE CLONED KV1.2 K+ CHANNEL( CHANNEL PEPTIDE TOXIN, INTERACTS WITH THE ALPHA)

The interaction between two nonhomologous K+ channel toxins, Tityus se rrulatus (scorpion) toxin tityustoxin-Kalpha (TsTX-Kalpha) and Dendroa spis angusticeps (snake) toxin dendrotoxin (alpha-DTX), was investigat ed on K+ currents in B82 fibroblast cells transformed to express the K v1.2 K+ channel. As demonstrated previously, alpha-DTX was a potent bl ocker of the K+ current (K(d), 2.8 nm). Recombinant TsTX-Kalpha produc ed a similar block of the current but was 1 order of magnitude more po tent (K(d), 0.21 nm). TsTX-Kalpha did not affect the kinetic propertie s of the current or its voltage dependence of activation. Experiments with excised and cell-attached patch recordings demonstrated that TsTX -Kalpha blocks the K+ channel by binding to an extracellular site. In the presence of TsTX-Kalpha the blocking potency of alpha-DTX was redu ced, whereas the potency of 4-aminopyridine, which also blocks the cha nnel, was unaffected. Alpha-DTX caused a rightward shift in the scaled concentration-response curve for TsTX-Kalpha, the magnitude of which was reasonably well predicted by a model in which there is a competiti ve interaction between the two peptide toxins. We conclude that TsTX-K alpha and alpha-DTX block the Kv1.2 K+ channel by binding to the same or closely related sites.